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Changes in intracranial pressure elicited by electrical stimulation of the brainstem reticular formation in spinal cats with vagotomy
Journal of the Autonomic Nervous System, 25 (1988) 155-164 Elsevier
155
JAN 00889
Changes in intracranial pressure elicited by electrical stimulation of the brainstem reticular formation in spinal cats with vagotomy Masanobu Maeda Department of Physiology, Osaka City UniversityMedical School, Abeno-ku Osaka (Japan) (Received 13 June 1988) (Revised version received and accepted 10 October 1988)
Key words: Cerebrovascular circulation; Brainstem; Intracranial pressure; Cat; Electrical stimulation
Abstract The momentary changes in intracranial pressure (ICP) were explored using electrical stimulation of the brainstem reticular formation and the nucleus fastigii of the cerebellum in cats under artificial ventilation after spinalization (C2) and vagotomy. Regions that yielded an increase in ICP in the arterial pressor area were: the central part of the pontine reticular formation, the dorsal medullary reticular formation, the central part of the medullary reticular formation, and the nucleus fastigii of the cerebellum; and one region in the arterial depressor area was the paramedial and ventral medial region of the medullary reticular formation. Since the arterial blood pressure and respiration was maintained constant during electrical stimulation by spinalization and vagotomy, the increase in ICP in the cranium, a semi-closed box, momentarily reflected an increase in cerebral blood volume due to cerebral vasodilatation. It is suggested that excitation of cell bodies or fibres within these regions may produce cerebral vasodilatation.
Introduction The effects of focal electrical stimulation of the brainstem on the intracranial pressure (ICP) and arterial b l o o d pressure (ABP) have been extensively examined in the cat [13-15,17], a n d later, in the dog [6]. Furthermore, the effects of stimulating cerebral cortex and h y p o t h a l a m u s have been examined in the cat [15,16]. It was shown that the early change in ICP p r o d u c e d by the electrical stimulation was influenced b y the change in cerebral blood volume (CBV) due to neurogenic cerebral vasodilatation or vasoconstriction a n d the
Correspondence: M. Maeda, Department of Physiology, Osaka City University Medical School, 1-4-54, Asahi-machi, Abenoku, Osaka 545, Japan.
change in driving pressure caused b y the associated alteration of A B P and respiratory movement [15]. W h e n b o t h A B P and ICP increased in these studies, it could not be determined whether the change in I C P was due to neurogenic cerebral vasodilatation or due to a rise in ABP. If the A B P and respiration are sustained at steady levels during electrical stimulation, the change in ICP m o m e n t a r i l y reflects the change in CBV due to vasodilatation. A n increase in cerebral blood flow (CBF) has been d e m o n s t r a t e d following electrical stimulation of the b r a i n s t e m [9,10,18,19]. Recently, the investigation of the detailed anatomical locations which p l a y a role in the control of cerebral circulation has been started. Electrical stimulation of the nucleus fastigii of the cerebellum [20,21], the dorsal medullary reticular formation [7,8], and the
0165-1838/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
156 nucleus tractus solitarii [22] was found to increase the cortical blood flow in rats. In these studies, at least 30 s was required to measure the CBF, so that the experimental design adopted did not permit moment-to-moment observation of rapid changes in the responses of the cerebral vessels [22]. The present study was undertaken to explore extensively the momentary changes in ICP in response to brainstem activation by focal electrical stimulation in spinalized and vagotornized cats, in which no change in ABP and respiration was produced during the brainstem activation. By this exploration, it is possible to deduce the locations of the regions which may be related to cerebral vasodilatation in the brainstem reticular formation of the cat.
Materials and Methods Preparation of animals
Experiments were performed on 40 mongrel cats of either sex weighing 3.8 + 0.7 kg (mean ± S.D.). Anesthesia was induced by an i.p. injection of urethane (500 m g / k g ) and chloralose (50 mg/kg). Supplementary doses of chloralose were given intermittently via the cannulated right femoral vein. The depth of anesthesia was assessed by monitoring the changes in heart rate (HR) and A B E Care was taken to ensure that sudden cardiovascular responses did not occur to noxious stimuli. The depth of anesthesia was also assessed from a parietal electroencephalograph (EEG) which was monitored on an oscilloscope (Nihon Kohden, VC-10) or a polygraph recorder (Nihon Kohden, WS-681G). The animal was immobilized by intermittent injection of pancuronium bromide at 0.1 mg. kg -1 • h-a). The trachea was intubated and artificial ventilation was carried out. Body temperature was monitored and maintained at about 37 ° C with a heating lamp. The ABP was recorded from a cannula inserted into the abdominal aorta through the right femoral artery via a strain-gauge transducer (Nihon Kohden, TP-101T) connected to a carrier amplifier (Nihon Kohden, AP-601G). The H R was counted with a heart rate counter (Nihon Kohden, AT-601G). The central venous pressure (CVP) was
recorded from a cannula inserted into the cranial vena cava. The end-tidal CO 2 was recorded using an infrared CO 2 analyser (Nihon Kohden, OIR7101). The head of the animal was then fixed in a stereotaxic head holder. The tCP was recorded from a polyethylene tube inserted into the left lateral ventricle through a burr hole made in the left parietal bone. The burr hole was filled completely with carboxylate cement. The CBF was recorded from a thermocouple probe placed in the right parietal lobe by means of a thermal clearance cerebral blood flow meter (Shinei, CTE-202) connected to a DC amplifier (Nihon Kohden, AD641G). In 16 cats, the local cerebral blood volume (CBV) was recorded by means of the photoelectric method described by Tomita et al. [28]. A miniature lamp was implanted in the right occipital lobe, and the intensity of light transmitted through the cerebral tissue was monitored from the brain surface with a photodiode connected to a DC amplifier. The intensity of the transmitted light was quantified for CBV. An EEG was monitored from a stainless steel screw inserted through the skull so as to lie on the dura over the parietal cortex. The recording was monopolar. The ABP. HR, CVP, ICP. EEG. end-tidal CO,, CBF, and CBV were continuously recorded on a multipurpose polygraph recorder. The arterial pH, p C O 2 and PO2 were frequently measured and maintained within the physiological range (Table Ij. Electrical stimulation
Electrical stimulation was performed with a concentric electrode. A stainless-steel cannula, insulated except for the tip, had a core made of tungsten wire insulated except for the tip, which protruded approximately 1 rnm beyond the end of the cannula. The electrode was inserted into the brainstem at an angle of 45 ° to the horizontal TABLE I Blood gases in anesthetized and paralyzed cats
pH 7.380+ 0.051
p CO2 36.5 ± 3.9
p 02 98.6 ± 13.2
n 40
Values are means+ S.D. pCO2, partial pressure of CO~; PO2, partial pressure of 02; n, number of e x i t s .
157 plane, so as to avoid the tentorium cerebelli. It was lowered in small steps (1 or 0.5 mm) via a small burr hole drilled through the skull. The core tip delivered negative square pulses of 0.4 ms duration at 40 Hz from a constant current stimulator (Nihon Kohden, SEN-3201) and an isolation unit (Nihon Kohden, SS-102J). The stimulus current was measured by passing the stimulus output across a 100 I2 resistor and displayed on an oscilloscope. The intensity of the electrical pulses was 200 #A. The atlases of Snider and Niemer [26], Taber [27], and Haba [5] were employed for stereotaxic stimulation.
Experimental procedure Laminectomy of the second and third cervical vertebrae was performed and a thread was passed below the second segment of the cervical cord. Care was taken not to impair the dura mater of the spinal cord so as to avoid any leakage of CSF. As a control, electrical stimulation was performed without spinalization and vagotomy. The cervical vago-sympathetic trunks were then cut bilaterally, and the cervical spinal cord was tied at the C 2 level. The abdominal aorta was previously exposed and a thread was passed below it. When the cordotomy was performed, ABP transiently increased at first and then decreased. Exsanguination was performed to prevent the first rapid transient hypertension which may cause cerebral vasoparalysis [22]. Then, the abdominal aorta was occluded, and plasma substitute with hydroxyethyl starch (Kyorin, Hespander inj.) was infused, and the blood from the same cat was transfused to prevent hypotension. Following the spinalization and vagotomy, the same stimulus as the control one was repeated at the same brainstem sites.
tively, it was embedded in paraffin and sectioned. The stimulation tracts and sites were identified in sections and stained using the Kltiver-Barrera method or Neutral red.
Results
Control responses by electrical stimulation of the brainstem In the control, electrical stimulation was applied to a total of 627 sites in 40 cats without spinalization and vagotomy. Then, after the spinalization and vagotomy had been performed, the stimulation was repeated in 624 out of the 627 sites. The ABP increased in 265 out of the 627 sites in the control (Figs. 1A and 2A). The distribution of pressor sites is shown on the diagrammatic sections at angles of 45 ° to the horizontal plane in Figs. 5 and 6. Filled squares indicate the sites which, when stimulated with a 12-s train of pulses, elicited an increase in mean ABP of 50 mm Hg or greater; and filled rectangles, sites which, on stimulation, elicited an increase in mean ABP of less than 50 m m Hg (Figs. 5 and 6, left-hand sections). The ICP was increased in 246 out of the 265 pressor sites and was unchanged in the other
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Histology One or two key sites of stimulation were marked by the passage of a 20 #A DC current for 60 s through the stimulating electrode. At the end of each experiment, the animal was killed by giving a high dose of sodium pentobarbitone (about 100 mg/kg). The brain was fixed by perfusion of 10% formol-saline. It was then placed in sucrose-gum arabic solution overnight and serial sections (about 50 #m) were cut on a freezing microtome. Alterna-
.,
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Fig. 1. Kesponses to electrical stimulation of a site within the dorsal medullary reticular formation. A: control response without spinalization and vagotomy.B: response after spinalization and vagotomy.Traces from above: cerebral blood flow, arterial blood pressure, intracranial pressure, cerebral blood volume, heart rate, central venous pressure and end-tidal CO2. The periods of stimulation are indicated by the horizontal bars.
158 A CBF
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Fig. 2. Responses to electrical stimulation of a site within the rostral ventrolateral medullary reticular formation. A: control response without spinalization and vagotomy. B: response after spinalization and vagotomy. Traces as in Fig. 1. The periods of stimulation are indicated by the horizontal bars.
19 sites. For example, in the experiment in Fig. 1A, electrical stimulation applied to a dorsomedial site in the medulla oblongata reticular formation produced increases in ABP, ICP, CBF, and CBV. In the experiment in Fig. 2A, electrical stimulation applied to a ventrolateral site in the medulla produced increases in ABE ICP, CBF, and CBV. Since the animals were paralyzed with pancuronium bromide and artificially ventilated, their respiration and CVP did not change during the stimulation. The ABP fell in 62 out of the 627 sites (Fig. 3A). In Figs. 5 and 6, large filled ovals indicate the sites which elicited a decrease in mean ABP of 25 mm Hg or greater, and small filled ovals, those eliciting a decrease in mean ABP of less than 25 mm Hg. The ICP was increased in 9 out of the 62
30s
Fig. 3. Responses to electrical stimulation of a site within the paramedial region of the medullary reticular formation. A: control response without spinalization and vagotomy. B: response after spinalization and vagotomy. Traces as in Fig. 1. The periods of stimulation are indicated by the horizontal bars.
depressor sites, fell in 22, and was unchanged in the other 31 sites. In the experiment in Fig. 3A, electrical stimulation applied to a paramedial site in the medullary reticular formation produced decreases in ABP, ICP, CBF, and HR. Electrical stimulation of the brainstem in cats with spinalization and vagotomy Electrical stimulation was applied to a total of 624 sites in 40 cats after spinatization and vagotomy. The ICP increased in 174 out of the 624 sites despite no change in ABE The CBV was simultaneously recorded in 60 out of the 174 sites, and showed an increase in 44 out of the 60 sites (73%), but there was no change in the other 16 sites (27%). The sites investigated were classified into 3 groups according to the control patterns of ABP response: 262 arterial pressor sites, 62 arterial depressor sites and 300 no response sites of which
TABLE II Relationship between responses of arterial blood pressure in the control and respanses of intracranial pressure [ollowing spinalization and vagotomy Response pattern
Stimulation sites
spinalization and vagotomy
Pressor area
Depressor area
No ~
Increase in ICP
108 (41%) 3 (1%) 151 (58%)
32 (52%) 0 (0%) 30 (48%)
34 (I1%) 0 (0%) 266 (89%)
174 3 447
262
62
300
624
Deerease inICP No chanse in ICP
Total in ABP
159 stimulation produced no change in ABP (Table II). There were 3 principal regions which yielded an increase in ICP following spinalization and vagotomy in the arterial pressor area of the brainstem reticular formation: the central part of the pontine reticular formation, the dorsal medullary reticular formation, and the central part of the medullary reticular formation (Figs. 5 and 6, right-hand sections). The central part of the pontine reticular formation constitutes the area extending from the nucleus pontis centralis oralis to the nucleus pontis centralis caudalis. The dorsal medullary reticular formation corresponds mainly to the nucleus parvocellularis and the dorsal part of the nucleus gigantocellularis. The central part of the medullary reticular formation corresponds mainly to the nucleus medullae oblongatae centralis subnucleus ventralis. An increase in ICP was produced following spinalization and vagotomy in 7 out of 9 sites in the dorsomedial medullary reticular formation of which stimulation elicited an increase in mean ABP of 50 mm Hg or greater in the control response. In the experiment in Fig. 1B, after spinalization and vagotomy, the same stimulation as the control produced increases in ICP, CBV, and CBF with no change in ABP and HR. There were few sites in which stimulation after spinalization and vagotomy produced an increase in ICP in the rostral ventrolateral medullary reticular formation. Out of 14 sites in the ventrolateral medullary reticular formation of which stimulation produced an increase in mean ABP of 50 mm Hg or greater in the control, only one site elicited an increase in ICP following spinalization and vagotomy. For example, in the experiment in Fig. 2B, electrical stimulation applied to a rostral ventrolateral site produced no change in ICP, CBV, and CBF after spinalization and vagotomy. The region that yielded an increase in ICP following spinalization and vagotomy in the arterial depressor area was the paramedial or ventral medial region of the medullary reticular formation (Fig. 3B). This region corresponds mainly to the nucleus paramedium reticularis or the nucleus raphe pallidus.
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Fig. 4. Responses to electrical stimulation of a site within the nucleus fastigii. A: control response without spinalization and vagotomy.B: responseafter spinalization and vagotomy.Traces as in Fig. 1. The periods of stimulation are indicated by the horizontal bars.
Relationship between increase in ICP e#cited by electrical stimulation in spinalized and vagotomized cats and the appearance of an EEG arousal pattern Continuous recording of EEG on a polygraph recorder was performed at 517 stimulation sites in 30 cats. Low voltage and high frequency electrical activity was observed during electrical stimulation and was regarded as representing the arousal pattern of the EEG. It was detected in 25 (96%) out of 26 sites at which electrical stimulation produced an increase in ICP after spinalization and vagotomy in the central part of the pontine reticular formation and the EEG was simultaneously recorded on the polygraph, in 4 (15%) out of 27 sites in the dorsal medullary reticular formation, and in 7 (41%) out of 17 sites in the central part of the medullary reticular formation. Electrical stimulation of the nucleus fastigii of the cerebellum Electrical stimulation of the nucleus fastigii was carried out at a total of 13 sites in 6 cats (Fig. 4). In the control, rises in ABP and ICP were produced at all sites. Following spinalization and vagotomy, electrical stimulation produced an increase in ICP despite no change in ABP in 10 out of 13 sites. The CBV was simultaneously recorded in 5 out of
160
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Figs. 5 and 6. Schematic drawing of the electrically stimulated sites presented in coronal sections (45 o to the horizontal plane) of the cat brainstem. The results were obtained from 40 cats without spinalization and vagotomy (left-hand sections. 627 sites) and with spinalization and vagotomy (right-hand sections, 624 sites). Each section passes through the sites of the antero-posterior and horizontal coordinates following the atlas of Snider and Niemer [26]. Symbols are as follows. Control cats: II. pressor site with a mean arterial blood pressure (ABP) of 50 mm Hg or greater; l pressor site with a mean ABP of less than 50 mm Hg; O, depressor site with a mean ABP of 25 mm Hg or greater; o , depressor site with a mean ABP of less than 25 mm Hg. Spinaliz~ and vagotomized cats: ra, arterial pressor site; (3, arterial depressor site; A, site which yielded an increase in intracranial pressure (tCP) after spinalization and vagotomy; v, site which yielded a decrease in ICP after spinalization and vagotomy; ×. site which yielded no change in ICP after spinalization and vagotomy. Be, braehium conjunetivum: Bp, brachium pontis; Cv. n. med~ae oblongatae centralis subnueleus ventralis; Fire, fasciculus longitudinalis medialis; Frm. formatio reticularis mesencephali; Go, n. gigantocellularis; Gcp, gfiseum centrale pomis; Lm, lemniscus medialis; Oi, n. olivaris inferior; Os, n. olivaris superior; P. tractus pyramidalis: Pc. n. parvocellularis; Pro, n. paramedium reticularis; Pmd. n. paramedium retieularis subnucleus dorsalis: Pray. n. paramedium reticularis subnucleus ventralis; Poc, n. pontis centralis caudalis; Poo. n. pontis centralis oralis; Rpa, n. raphe pallidus.
the 10 sites a n d was increased in all sites. I n the o t h e r 3 o u t o f the 13 sites, the I C P u n d e r w e n t n o change.
Discussion C h a n g e s in I C P p r o d u c e d b y electrical stimulation of the b r a i n s t e m are i n f l u e n c e d b y c h a n g e s in
A B P a n d respiration, o r changes in C B V d u e to n e u r o g e n i c c e r e b r a l v a s o d i l a t a t i o n or v a s o c o n s t r i c t i o n i n d u c e d by the s t i m u l a t i o n [13,15]. Thus, the p r o c e d u r e of s p i n a l i z a t i o n a n d vagoto m y rules o u t the s e c o n d a r y effects caused by changes in A B P o r respiration. T h e I C P is inf l u e n c e d by c h a n g e s in c e r e b r o s p i n a l fluid ( C S F ) v o l u m e , c e r e b r a l tissue volume, and C B V in the
161 P3, H -10
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cranium which forms a semi-closed box. Though the electrical stimulation of the sympathetic trunks in the neck during 1-2 h reduces the rate of CSF formation [11], the CSF and cerebral tissue volumes do not increase or decrease momentarily as a result of electrical stimulation. If neurogenic cerebral vasodilatation or vasoconstriction occurs due to a change in the brainstem neural activities in cats with spinalization and vagotomy, the CBV undergoes a change and the ICP momentarily reflects it. It has been reported previously that electrical stimulation of the nucleus fastigii produced cerebral vasodilatation [20,21]. Electrical
stimulation of the nucleus fastigii in cats with spinalization and vagotomy produced an increase in ICP, which may represent cerebral vasodilatation. In fact, when increases in ICP were produced in such animals, the CBV increased in 73% of the cases. The CBV underwent no change in the other 27%. The reason may be that the CBV was measured as the local CBV and not the whole brain CBV, because the distribution of increases in regional CBF elicited by electrical stimulation is not homogeneous [7]. The CBF was monitored by means of thermal clearance technique, by which the CBF can be continuously recorded. But it is
162
measured as the local CBF and the absolute value cannot be known by means of this technique. It remains to be determined whether the increase in ICP elicited by the stimulation in the present study is due to the dilatation of cerebral arteries or veins. When a miniature lamp was implanted in the cerebral cortex for measuring the CBV, it was placed at the site where photodiode does not receive the light directly transmitted through the cerebral vein. When cerebral angiograms were taken during a rise in ICP, it showed wider vessels in the arterial phase as compared with angiograms taken during the period without a rise in ICP [12]. It seems unlikely therefore that the increases in ICP and CBV observed in this study are due to the dilatation of cerebral veins. According to the distance-current relationship of electrical stimulation reported by Comte [3], the distance of the spread of the stimulus current is about 1 mm at 200/~A. There were many sites of which stimulation produced different responses as compared with those at distance of 1.0 mm in the present study. An increase in ICP was frequently observed by stimulation of the arterial pressor or depressor sites, but scarcely in the sites which were not related to control of the systemic arterial blood pressure. This indicates that the anatomical location of the sites which control the cerebral circulation is mainly related to the area which controls the systemic circulation. No change in ICP was frequently observed also in the arterial pressor or depressor sites. This suggests that all sites controlling the systemic circulation are not related to the control of cerebral vasodilatation. An increase in CBF has been demonstrated following electrical stimulation of the brainstem [7-10,18,19,22]. It is suggested that the cerebral vasodilator pathways from the brainstem are mediated by the following two routes. One is the intrinsic cerebral vasodilator pathway. This represents an action on the blood vessels of neurons whose processes are entirely contained within the central nervous system [23]. Increases in CBF elicited by electrical stimulation of the nucleus fastigii or the dorsal medullary reticular formation are thought to be mediated by this pathway [7,21,23]. The other route is the peripheral cerebral vasodilator path-
way mediated by branches of the seventh cranial nerve or other cranial nerves [1,2,4,29]. In the present study, these cerebral vasodilator pathways were intact, so that no region related to cerebral vasodilatation was excluded. It has been reported that the increase in local CBF elicited by stimulation of the dorsal medullary reticular formation was accompanied by a corresponding and proportional increase in local cerebral glucose utilization and it is reasonable to assume that the cerebral vasodilatation induced by stimulation of the dorsal medullary reticular formation is a consequence of an increase of cerebral metabolism [8]. However, it has also been pointed out that this measurement of the flow and metabolism may not provide an accurate reflection of the observed phenomena because of the large difference (flow, 30 s; metabolism, 45 min) in the stable period over which each variable was measured [25]. It remains to be determined whether increases in ICP and CBV elicited by the stimulation in the present study are coupled to changes in metabolism. However. changes in ICP and CBV were observed soon after the beginning of the stimulation, and it is difficult to consider that changes of metabolism would occur within such a short time (within a few seconds) and immediately reflect the cerebral vessel response. It seems unlikely therefore that the responses elicited in this study were due to a change in metabolism. In the past, it was found that only an EEG arousal response produced by electrical stimulation of the brainstem was accompanied by an increase in cortical blood flow [9]. On the other hand, electrical stimulation of the dorsal medullary reticular formation, which produced an increase in CBF, did not alter the EEG [8]. Iadecola et al. [8] proposed that these conflicting observations might indicate the existence of two separate functional systems in the brainstem. In the present study, the arousal pattern was mostly observed in the central part of the pontine reticular formation, but scarcely in the dorsal meduUary reticular formation. Our results support the idea of Iadecola et al. It has been reported that the neurons of the rostral ventrolateral medullary reticular formation project into the intermediolateral column of the spinal cord and that this region is the origin of
163 s y m p a t h e t i c activities [24]. I n this region, t h e r e w e r e o n l y few sites of w h i c h electrical s t i m u l a t i o n y i e l d e d a n i n c r e a s e i n I C P i n cats w i t h s p i n a l i z a tion and vagotomy. The region does not therefore s e e m to b e r e l a t e d to t h e c e r e b r a l v a s o d i l a t a t i o n . On the other hand, the dorsal medullary reticular f o r m a t i o n is a p p a r e n t l y r e l a t e d to t h a t f u n c t i o n . These results imply that the brainstem reticular f o r m a t i o n in t h e a r t e r i a l p r e s s o r a r e a d o e s n o t c o n t r o l t h e c e r e b r a l v a s c u l a r t o n u s in a u n i f o r m fashion.
Acknowledgements T h e a u t h o r is g r a t e f u l to P r o f e s s o r S. M a t s u u r a a n d Dr. M. N a k a i for t h e i r critical r e a d i n g of t h e m a n u s c r i p t . H e also w i s h e s to t h a n k M e s s r s . T. K o n i s h i , T. K i t a n o , K. N i s h i m a k i a n d T. Yamamoto, medical students at Osaka City Univ e r s i t y M e d i c a l School, for t h e i r t e c h n i c a l assist a n c e . T h i s w o r k was s u p p o r t e d in p a r t b y a G r a n t - i n - A i d for Scientific R e s e a r c h f r o m t h e M i n i s t r y o f E d u c a t i o n , S c i e n c e a n d C u l t u r e of Japan.
References l Chorobski, J. and Penfield, W., Cerebral vasodilator nerves and their pathway from the medulla oblongata with observations on the pial and intracerebral vascular plexus, Arch. Neurol. Psychiat~, 28 (1932) 1257-1289. 2 Cobb, S. and Finesinger, J.E, Cerebral circulation. XIX. The vagal pathway of the vasodilator impulses, Arch. Neurol. Psychiat~, 28 (1932) 1243-1256. 3 Comte, P., Monopolar versus bipolar stimulation, AppL Neurophysiol., 45 (1982) 156-159. 4 D'Alecy, L.G. and Rose, C.J., Parasympathetic cholinergic control of cerebral blood flow in dogs, Circ. Res., 41 (1977) 324-331. 5 Haba, K., A stereotaxic atlas of lower brainstem of the cat, J. Juzen Med. Soc., 87 (1978) 135-183. 6 Hayashi, M., Ishii, H., Handa, Y., Kobayashi, H., Kawano, H. and Kabuto, M., Role of the medulla oblongata in plateau-wave development in dogs, J. Neurosurg., 67 (1987) 97-101. 7 ladecola, C., Nakai, M., Arbit, E. and Reis, D.J., Global cerebral vasodilatation elicited by focal electrical stimulation within the dorsal medullary reticular formation in anesthetized rat, J. Cereb. Blood Flow Metab., 3 (1983) 270-279.
8 ladecola, C., Nakai, M., Mraovitch, S., Ruggiero, D.A., Tucker, L.W. and Reis, D.J., Global increase in cerebral metabolism and blood flow produced by focal electrical stimulation of dorsal medullary reticular formation in rat, Brain Res., 272 (1983) 101-114. 9 Ingvar, D.H. and S~Sderberg, U., Cortical blood flow related to EEG patterns evoked by stimulation of the brain stem, Acta Physiol. Scand., 42 (1958) 130-143. 10 Langfitt, T.W. and Kassell, N.F., Cerebral vasodilatation produced by brain-stem stimulation: neurogenic control vs. autoregulation, Am. J. Physiol., 215 (1968) 90-97. 11 Lindvall, M., Edvinsson, L. and Owman, C., Sympathetic nervous control of cerebrospinal fluid production from the choroid plexus, Science, 201 (1978) 176-178. 12 Lundberg, N., Cronqvist, S. and Kjallquist, A., Clinical investigations on interrelations between intracranial pressure and intracranial hemodynamics. In W. Lukyendijk (Ed.), Progress in Brain Research. Vol 30, Elsevier, Amsterdam, 1968, pp. 70-75. 13 Maeda, M., Matsuura, S., Tanaka, K. and Nishimura, S., Plateau waves and cerebral autoregulation, J. Cereb. Blood Flow Metab. (Suppl. 1), 5 (1985) $65-$66. 14 Maeda, M., Tanaka, K., Nishimura, S. and Matsuura, S., Pressure wave-like changes in ICP produced by electric stimulation of the brainstem, hypothalamus and cerebral cortex in cats. In J.D. Miller, G.M. Teasdale, J.O. Rowan, S.L. Galbraith and A.D. Mendelow (Eds.), Intracranial Pressure VI, Springer, Berlin, 1986, pp. 156-160. 15 Maeda, M., Matsuura, S., Tanaka, K., Katsuyama, J., Nakamura, T., Sakamoto, H. and Nishimura, S., Effects of electrical stimulation on intracranial pressure and systemic arterial blood pressure in cats. Part 1. Stimulation of brain stem, Neurol. Res., 10 (1988) 87-92. 16 Maeda, M., Matsuura, S., Tanaka, K., Katsuyama, J. and Nishimura, S., Effects of electrical stimulation on intracranial pressure and systemic arterial blood pressure in cats. Part II. Stimulation of cerebral cortex and hypothalamus, Neurol. Res., 10 (1988) 93-96. 17 Matsuura, S., Kuno, M., Yasunami, T. and Maeda, M., Changes in intracranial pressure and arterial blood pressure following electric stimulation to restricted regions in the cat brainstem, Jpn. J. Physiol., 36 (1986) 857-869. 18 Meyer, J.S., Nomura, F., Sakamoto, K. and Kondo, A., Effect of stimulation of the brain-stem reticular formation on cerebral blood flow and oxygen consumption, Electroencephalogr. Clin. Neurophysiol., 26 (1969) 125-132. 19 Meyer, J.S., Teraura, T., Sakamoto, K. and Kondo, A., Central neurogenic control of cerebral blood flow, Neurology, 21 (1971) 247-262. 20 Nakai, M., Iadecola, C. and Reis, D.J., Global cerebral vasodilatation by stimulation of rat fastigial cerebellar nucleus, Am. J. Physiol., 243 (1982) H226-H235. 21 Nakai, M., ladecola, C., Ruggiero, D.A., Tucker, L.W. and Reis, D.J., Electrical stimulation of cerebellar fastigial nucleus increases cerebral cortical blood flow without change in local metabolism: evidence for an intrinsic system in brain for primary vasodilatation, Brain Res., 260 (1983) 35-49.
164 22 Nakai, M., An increase in cerebral blood flow elicited by electrical stimulation of the solitary nucleus in rats with cervical cordotomy and vagotomy, Jpn. J. Physiol., 35 (1985) 57-70. 23 Reis, D.J., Central neural control of cerebral circulation and metabolism. In E.T. Mackenzie, J. Seylaz and A. B+s (Eds.), Neurotransrnitters and the Cerebral Circulation. Raven, New York, 1984, pp. 91-119. 24 Reis, D.J., Granata, A.R., Job, T.H., Ross, C.A., Ruggiero, D.A. and Park, D.H., Brainstem catecholamine mechanisms in tonic and reflex control of blood pressure, Hypertension (Suppl. II), 6 (1984) II-7-11-15. 25 Seylaz, J., Pinard, E. and Mraovitch, S., Influence of specific intracerebral structures on the regulation of cerebral circulation. In C. Owman and J.E. Hardebo (Eds.), Neural Regulation of Brain Circulation, Elsevier Science Publishers
26 27
28
29
B.V. (Biomedical Divisioni, Amsterdam, New York, Oxford, 1986, pp. 147-167. Snider, R.S. and Niemer, W.T., A..gtereotaxic Atla.~ of the Cat Brain, The University of Chicago Press. Chicago, 196t Taber, E., The cytoarchitecture of the brainstem of the cat. I. Brainstem nuclei of cat. J. Comp. Neurol.. 116 t'1961} 27-69. Tomita, M., Gotoh, F., Sato, T., Amano, "1-.,Tanahashi, N., Tanaka, K. and Yamamoto, M., Photoelectric method for estimating hemodynamic changes ill regional cerebral tissue, Am. J. Physiol., 235 (1978) H56-H63. Waiters, B.B., Gillespie, S.A. and Moskowitz. M.A., Cerebrovascular projections from the sphenopalatine and otic ganglia to the middle cerebral artery, of the cat. Stroke, 17 (1986) 488 494.
155
JAN 00889
Changes in intracranial pressure elicited by electrical stimulation of the brainstem reticular formation in spinal cats with vagotomy Masanobu Maeda Department of Physiology, Osaka City UniversityMedical School, Abeno-ku Osaka (Japan) (Received 13 June 1988) (Revised version received and accepted 10 October 1988)
Key words: Cerebrovascular circulation; Brainstem; Intracranial pressure; Cat; Electrical stimulation
Abstract The momentary changes in intracranial pressure (ICP) were explored using electrical stimulation of the brainstem reticular formation and the nucleus fastigii of the cerebellum in cats under artificial ventilation after spinalization (C2) and vagotomy. Regions that yielded an increase in ICP in the arterial pressor area were: the central part of the pontine reticular formation, the dorsal medullary reticular formation, the central part of the medullary reticular formation, and the nucleus fastigii of the cerebellum; and one region in the arterial depressor area was the paramedial and ventral medial region of the medullary reticular formation. Since the arterial blood pressure and respiration was maintained constant during electrical stimulation by spinalization and vagotomy, the increase in ICP in the cranium, a semi-closed box, momentarily reflected an increase in cerebral blood volume due to cerebral vasodilatation. It is suggested that excitation of cell bodies or fibres within these regions may produce cerebral vasodilatation.
Introduction The effects of focal electrical stimulation of the brainstem on the intracranial pressure (ICP) and arterial b l o o d pressure (ABP) have been extensively examined in the cat [13-15,17], a n d later, in the dog [6]. Furthermore, the effects of stimulating cerebral cortex and h y p o t h a l a m u s have been examined in the cat [15,16]. It was shown that the early change in ICP p r o d u c e d by the electrical stimulation was influenced b y the change in cerebral blood volume (CBV) due to neurogenic cerebral vasodilatation or vasoconstriction a n d the
Correspondence: M. Maeda, Department of Physiology, Osaka City University Medical School, 1-4-54, Asahi-machi, Abenoku, Osaka 545, Japan.
change in driving pressure caused b y the associated alteration of A B P and respiratory movement [15]. W h e n b o t h A B P and ICP increased in these studies, it could not be determined whether the change in I C P was due to neurogenic cerebral vasodilatation or due to a rise in ABP. If the A B P and respiration are sustained at steady levels during electrical stimulation, the change in ICP m o m e n t a r i l y reflects the change in CBV due to vasodilatation. A n increase in cerebral blood flow (CBF) has been d e m o n s t r a t e d following electrical stimulation of the b r a i n s t e m [9,10,18,19]. Recently, the investigation of the detailed anatomical locations which p l a y a role in the control of cerebral circulation has been started. Electrical stimulation of the nucleus fastigii of the cerebellum [20,21], the dorsal medullary reticular formation [7,8], and the
0165-1838/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
156 nucleus tractus solitarii [22] was found to increase the cortical blood flow in rats. In these studies, at least 30 s was required to measure the CBF, so that the experimental design adopted did not permit moment-to-moment observation of rapid changes in the responses of the cerebral vessels [22]. The present study was undertaken to explore extensively the momentary changes in ICP in response to brainstem activation by focal electrical stimulation in spinalized and vagotornized cats, in which no change in ABP and respiration was produced during the brainstem activation. By this exploration, it is possible to deduce the locations of the regions which may be related to cerebral vasodilatation in the brainstem reticular formation of the cat.
Materials and Methods Preparation of animals
Experiments were performed on 40 mongrel cats of either sex weighing 3.8 + 0.7 kg (mean ± S.D.). Anesthesia was induced by an i.p. injection of urethane (500 m g / k g ) and chloralose (50 mg/kg). Supplementary doses of chloralose were given intermittently via the cannulated right femoral vein. The depth of anesthesia was assessed by monitoring the changes in heart rate (HR) and A B E Care was taken to ensure that sudden cardiovascular responses did not occur to noxious stimuli. The depth of anesthesia was also assessed from a parietal electroencephalograph (EEG) which was monitored on an oscilloscope (Nihon Kohden, VC-10) or a polygraph recorder (Nihon Kohden, WS-681G). The animal was immobilized by intermittent injection of pancuronium bromide at 0.1 mg. kg -1 • h-a). The trachea was intubated and artificial ventilation was carried out. Body temperature was monitored and maintained at about 37 ° C with a heating lamp. The ABP was recorded from a cannula inserted into the abdominal aorta through the right femoral artery via a strain-gauge transducer (Nihon Kohden, TP-101T) connected to a carrier amplifier (Nihon Kohden, AP-601G). The H R was counted with a heart rate counter (Nihon Kohden, AT-601G). The central venous pressure (CVP) was
recorded from a cannula inserted into the cranial vena cava. The end-tidal CO 2 was recorded using an infrared CO 2 analyser (Nihon Kohden, OIR7101). The head of the animal was then fixed in a stereotaxic head holder. The tCP was recorded from a polyethylene tube inserted into the left lateral ventricle through a burr hole made in the left parietal bone. The burr hole was filled completely with carboxylate cement. The CBF was recorded from a thermocouple probe placed in the right parietal lobe by means of a thermal clearance cerebral blood flow meter (Shinei, CTE-202) connected to a DC amplifier (Nihon Kohden, AD641G). In 16 cats, the local cerebral blood volume (CBV) was recorded by means of the photoelectric method described by Tomita et al. [28]. A miniature lamp was implanted in the right occipital lobe, and the intensity of light transmitted through the cerebral tissue was monitored from the brain surface with a photodiode connected to a DC amplifier. The intensity of the transmitted light was quantified for CBV. An EEG was monitored from a stainless steel screw inserted through the skull so as to lie on the dura over the parietal cortex. The recording was monopolar. The ABP. HR, CVP, ICP. EEG. end-tidal CO,, CBF, and CBV were continuously recorded on a multipurpose polygraph recorder. The arterial pH, p C O 2 and PO2 were frequently measured and maintained within the physiological range (Table Ij. Electrical stimulation
Electrical stimulation was performed with a concentric electrode. A stainless-steel cannula, insulated except for the tip, had a core made of tungsten wire insulated except for the tip, which protruded approximately 1 rnm beyond the end of the cannula. The electrode was inserted into the brainstem at an angle of 45 ° to the horizontal TABLE I Blood gases in anesthetized and paralyzed cats
pH 7.380+ 0.051
p CO2 36.5 ± 3.9
p 02 98.6 ± 13.2
n 40
Values are means+ S.D. pCO2, partial pressure of CO~; PO2, partial pressure of 02; n, number of e x i t s .
157 plane, so as to avoid the tentorium cerebelli. It was lowered in small steps (1 or 0.5 mm) via a small burr hole drilled through the skull. The core tip delivered negative square pulses of 0.4 ms duration at 40 Hz from a constant current stimulator (Nihon Kohden, SEN-3201) and an isolation unit (Nihon Kohden, SS-102J). The stimulus current was measured by passing the stimulus output across a 100 I2 resistor and displayed on an oscilloscope. The intensity of the electrical pulses was 200 #A. The atlases of Snider and Niemer [26], Taber [27], and Haba [5] were employed for stereotaxic stimulation.
Experimental procedure Laminectomy of the second and third cervical vertebrae was performed and a thread was passed below the second segment of the cervical cord. Care was taken not to impair the dura mater of the spinal cord so as to avoid any leakage of CSF. As a control, electrical stimulation was performed without spinalization and vagotomy. The cervical vago-sympathetic trunks were then cut bilaterally, and the cervical spinal cord was tied at the C 2 level. The abdominal aorta was previously exposed and a thread was passed below it. When the cordotomy was performed, ABP transiently increased at first and then decreased. Exsanguination was performed to prevent the first rapid transient hypertension which may cause cerebral vasoparalysis [22]. Then, the abdominal aorta was occluded, and plasma substitute with hydroxyethyl starch (Kyorin, Hespander inj.) was infused, and the blood from the same cat was transfused to prevent hypotension. Following the spinalization and vagotomy, the same stimulus as the control one was repeated at the same brainstem sites.
tively, it was embedded in paraffin and sectioned. The stimulation tracts and sites were identified in sections and stained using the Kltiver-Barrera method or Neutral red.
Results
Control responses by electrical stimulation of the brainstem In the control, electrical stimulation was applied to a total of 627 sites in 40 cats without spinalization and vagotomy. Then, after the spinalization and vagotomy had been performed, the stimulation was repeated in 624 out of the 627 sites. The ABP increased in 265 out of the 627 sites in the control (Figs. 1A and 2A). The distribution of pressor sites is shown on the diagrammatic sections at angles of 45 ° to the horizontal plane in Figs. 5 and 6. Filled squares indicate the sites which, when stimulated with a 12-s train of pulses, elicited an increase in mean ABP of 50 mm Hg or greater; and filled rectangles, sites which, on stimulation, elicited an increase in mean ABP of less than 50 m m Hg (Figs. 5 and 6, left-hand sections). The ICP was increased in 246 out of the 265 pressor sites and was unchanged in the other
,I
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.
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Histology One or two key sites of stimulation were marked by the passage of a 20 #A DC current for 60 s through the stimulating electrode. At the end of each experiment, the animal was killed by giving a high dose of sodium pentobarbitone (about 100 mg/kg). The brain was fixed by perfusion of 10% formol-saline. It was then placed in sucrose-gum arabic solution overnight and serial sections (about 50 #m) were cut on a freezing microtome. Alterna-
.,
(beats/min)
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150
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Fig. 1. Kesponses to electrical stimulation of a site within the dorsal medullary reticular formation. A: control response without spinalization and vagotomy.B: response after spinalization and vagotomy.Traces from above: cerebral blood flow, arterial blood pressure, intracranial pressure, cerebral blood volume, heart rate, central venous pressure and end-tidal CO2. The periods of stimulation are indicated by the horizontal bars.
158 A CBF
(pv)
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Fig. 2. Responses to electrical stimulation of a site within the rostral ventrolateral medullary reticular formation. A: control response without spinalization and vagotomy. B: response after spinalization and vagotomy. Traces as in Fig. 1. The periods of stimulation are indicated by the horizontal bars.
19 sites. For example, in the experiment in Fig. 1A, electrical stimulation applied to a dorsomedial site in the medulla oblongata reticular formation produced increases in ABP, ICP, CBF, and CBV. In the experiment in Fig. 2A, electrical stimulation applied to a ventrolateral site in the medulla produced increases in ABE ICP, CBF, and CBV. Since the animals were paralyzed with pancuronium bromide and artificially ventilated, their respiration and CVP did not change during the stimulation. The ABP fell in 62 out of the 627 sites (Fig. 3A). In Figs. 5 and 6, large filled ovals indicate the sites which elicited a decrease in mean ABP of 25 mm Hg or greater, and small filled ovals, those eliciting a decrease in mean ABP of less than 25 mm Hg. The ICP was increased in 9 out of the 62
30s
Fig. 3. Responses to electrical stimulation of a site within the paramedial region of the medullary reticular formation. A: control response without spinalization and vagotomy. B: response after spinalization and vagotomy. Traces as in Fig. 1. The periods of stimulation are indicated by the horizontal bars.
depressor sites, fell in 22, and was unchanged in the other 31 sites. In the experiment in Fig. 3A, electrical stimulation applied to a paramedial site in the medullary reticular formation produced decreases in ABP, ICP, CBF, and HR. Electrical stimulation of the brainstem in cats with spinalization and vagotomy Electrical stimulation was applied to a total of 624 sites in 40 cats after spinatization and vagotomy. The ICP increased in 174 out of the 624 sites despite no change in ABE The CBV was simultaneously recorded in 60 out of the 174 sites, and showed an increase in 44 out of the 60 sites (73%), but there was no change in the other 16 sites (27%). The sites investigated were classified into 3 groups according to the control patterns of ABP response: 262 arterial pressor sites, 62 arterial depressor sites and 300 no response sites of which
TABLE II Relationship between responses of arterial blood pressure in the control and respanses of intracranial pressure [ollowing spinalization and vagotomy Response pattern
Stimulation sites
spinalization and vagotomy
Pressor area
Depressor area
No ~
Increase in ICP
108 (41%) 3 (1%) 151 (58%)
32 (52%) 0 (0%) 30 (48%)
34 (I1%) 0 (0%) 266 (89%)
174 3 447
262
62
300
624
Deerease inICP No chanse in ICP
Total in ABP
159 stimulation produced no change in ABP (Table II). There were 3 principal regions which yielded an increase in ICP following spinalization and vagotomy in the arterial pressor area of the brainstem reticular formation: the central part of the pontine reticular formation, the dorsal medullary reticular formation, and the central part of the medullary reticular formation (Figs. 5 and 6, right-hand sections). The central part of the pontine reticular formation constitutes the area extending from the nucleus pontis centralis oralis to the nucleus pontis centralis caudalis. The dorsal medullary reticular formation corresponds mainly to the nucleus parvocellularis and the dorsal part of the nucleus gigantocellularis. The central part of the medullary reticular formation corresponds mainly to the nucleus medullae oblongatae centralis subnucleus ventralis. An increase in ICP was produced following spinalization and vagotomy in 7 out of 9 sites in the dorsomedial medullary reticular formation of which stimulation elicited an increase in mean ABP of 50 mm Hg or greater in the control response. In the experiment in Fig. 1B, after spinalization and vagotomy, the same stimulation as the control produced increases in ICP, CBV, and CBF with no change in ABP and HR. There were few sites in which stimulation after spinalization and vagotomy produced an increase in ICP in the rostral ventrolateral medullary reticular formation. Out of 14 sites in the ventrolateral medullary reticular formation of which stimulation produced an increase in mean ABP of 50 mm Hg or greater in the control, only one site elicited an increase in ICP following spinalization and vagotomy. For example, in the experiment in Fig. 2B, electrical stimulation applied to a rostral ventrolateral site produced no change in ICP, CBV, and CBF after spinalization and vagotomy. The region that yielded an increase in ICP following spinalization and vagotomy in the arterial depressor area was the paramedial or ventral medial region of the medullary reticular formation (Fig. 3B). This region corresponds mainly to the nucleus paramedium reticularis or the nucleus raphe pallidus.
c.
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Fig. 4. Responses to electrical stimulation of a site within the nucleus fastigii. A: control response without spinalization and vagotomy.B: responseafter spinalization and vagotomy.Traces as in Fig. 1. The periods of stimulation are indicated by the horizontal bars.
Relationship between increase in ICP e#cited by electrical stimulation in spinalized and vagotomized cats and the appearance of an EEG arousal pattern Continuous recording of EEG on a polygraph recorder was performed at 517 stimulation sites in 30 cats. Low voltage and high frequency electrical activity was observed during electrical stimulation and was regarded as representing the arousal pattern of the EEG. It was detected in 25 (96%) out of 26 sites at which electrical stimulation produced an increase in ICP after spinalization and vagotomy in the central part of the pontine reticular formation and the EEG was simultaneously recorded on the polygraph, in 4 (15%) out of 27 sites in the dorsal medullary reticular formation, and in 7 (41%) out of 17 sites in the central part of the medullary reticular formation. Electrical stimulation of the nucleus fastigii of the cerebellum Electrical stimulation of the nucleus fastigii was carried out at a total of 13 sites in 6 cats (Fig. 4). In the control, rises in ABP and ICP were produced at all sites. Following spinalization and vagotomy, electrical stimulation produced an increase in ICP despite no change in ABP in 10 out of 13 sites. The CBV was simultaneously recorded in 5 out of
160
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Figs. 5 and 6. Schematic drawing of the electrically stimulated sites presented in coronal sections (45 o to the horizontal plane) of the cat brainstem. The results were obtained from 40 cats without spinalization and vagotomy (left-hand sections. 627 sites) and with spinalization and vagotomy (right-hand sections, 624 sites). Each section passes through the sites of the antero-posterior and horizontal coordinates following the atlas of Snider and Niemer [26]. Symbols are as follows. Control cats: II. pressor site with a mean arterial blood pressure (ABP) of 50 mm Hg or greater; l pressor site with a mean ABP of less than 50 mm Hg; O, depressor site with a mean ABP of 25 mm Hg or greater; o , depressor site with a mean ABP of less than 25 mm Hg. Spinaliz~ and vagotomized cats: ra, arterial pressor site; (3, arterial depressor site; A, site which yielded an increase in intracranial pressure (tCP) after spinalization and vagotomy; v, site which yielded a decrease in ICP after spinalization and vagotomy; ×. site which yielded no change in ICP after spinalization and vagotomy. Be, braehium conjunetivum: Bp, brachium pontis; Cv. n. med~ae oblongatae centralis subnueleus ventralis; Fire, fasciculus longitudinalis medialis; Frm. formatio reticularis mesencephali; Go, n. gigantocellularis; Gcp, gfiseum centrale pomis; Lm, lemniscus medialis; Oi, n. olivaris inferior; Os, n. olivaris superior; P. tractus pyramidalis: Pc. n. parvocellularis; Pro, n. paramedium reticularis; Pmd. n. paramedium retieularis subnucleus dorsalis: Pray. n. paramedium reticularis subnucleus ventralis; Poc, n. pontis centralis caudalis; Poo. n. pontis centralis oralis; Rpa, n. raphe pallidus.
the 10 sites a n d was increased in all sites. I n the o t h e r 3 o u t o f the 13 sites, the I C P u n d e r w e n t n o change.
Discussion C h a n g e s in I C P p r o d u c e d b y electrical stimulation of the b r a i n s t e m are i n f l u e n c e d b y c h a n g e s in
A B P a n d respiration, o r changes in C B V d u e to n e u r o g e n i c c e r e b r a l v a s o d i l a t a t i o n or v a s o c o n s t r i c t i o n i n d u c e d by the s t i m u l a t i o n [13,15]. Thus, the p r o c e d u r e of s p i n a l i z a t i o n a n d vagoto m y rules o u t the s e c o n d a r y effects caused by changes in A B P o r respiration. T h e I C P is inf l u e n c e d by c h a n g e s in c e r e b r o s p i n a l fluid ( C S F ) v o l u m e , c e r e b r a l tissue volume, and C B V in the
161 P3, H -10
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cranium which forms a semi-closed box. Though the electrical stimulation of the sympathetic trunks in the neck during 1-2 h reduces the rate of CSF formation [11], the CSF and cerebral tissue volumes do not increase or decrease momentarily as a result of electrical stimulation. If neurogenic cerebral vasodilatation or vasoconstriction occurs due to a change in the brainstem neural activities in cats with spinalization and vagotomy, the CBV undergoes a change and the ICP momentarily reflects it. It has been reported previously that electrical stimulation of the nucleus fastigii produced cerebral vasodilatation [20,21]. Electrical
stimulation of the nucleus fastigii in cats with spinalization and vagotomy produced an increase in ICP, which may represent cerebral vasodilatation. In fact, when increases in ICP were produced in such animals, the CBV increased in 73% of the cases. The CBV underwent no change in the other 27%. The reason may be that the CBV was measured as the local CBV and not the whole brain CBV, because the distribution of increases in regional CBF elicited by electrical stimulation is not homogeneous [7]. The CBF was monitored by means of thermal clearance technique, by which the CBF can be continuously recorded. But it is
162
measured as the local CBF and the absolute value cannot be known by means of this technique. It remains to be determined whether the increase in ICP elicited by the stimulation in the present study is due to the dilatation of cerebral arteries or veins. When a miniature lamp was implanted in the cerebral cortex for measuring the CBV, it was placed at the site where photodiode does not receive the light directly transmitted through the cerebral vein. When cerebral angiograms were taken during a rise in ICP, it showed wider vessels in the arterial phase as compared with angiograms taken during the period without a rise in ICP [12]. It seems unlikely therefore that the increases in ICP and CBV observed in this study are due to the dilatation of cerebral veins. According to the distance-current relationship of electrical stimulation reported by Comte [3], the distance of the spread of the stimulus current is about 1 mm at 200/~A. There were many sites of which stimulation produced different responses as compared with those at distance of 1.0 mm in the present study. An increase in ICP was frequently observed by stimulation of the arterial pressor or depressor sites, but scarcely in the sites which were not related to control of the systemic arterial blood pressure. This indicates that the anatomical location of the sites which control the cerebral circulation is mainly related to the area which controls the systemic circulation. No change in ICP was frequently observed also in the arterial pressor or depressor sites. This suggests that all sites controlling the systemic circulation are not related to the control of cerebral vasodilatation. An increase in CBF has been demonstrated following electrical stimulation of the brainstem [7-10,18,19,22]. It is suggested that the cerebral vasodilator pathways from the brainstem are mediated by the following two routes. One is the intrinsic cerebral vasodilator pathway. This represents an action on the blood vessels of neurons whose processes are entirely contained within the central nervous system [23]. Increases in CBF elicited by electrical stimulation of the nucleus fastigii or the dorsal medullary reticular formation are thought to be mediated by this pathway [7,21,23]. The other route is the peripheral cerebral vasodilator path-
way mediated by branches of the seventh cranial nerve or other cranial nerves [1,2,4,29]. In the present study, these cerebral vasodilator pathways were intact, so that no region related to cerebral vasodilatation was excluded. It has been reported that the increase in local CBF elicited by stimulation of the dorsal medullary reticular formation was accompanied by a corresponding and proportional increase in local cerebral glucose utilization and it is reasonable to assume that the cerebral vasodilatation induced by stimulation of the dorsal medullary reticular formation is a consequence of an increase of cerebral metabolism [8]. However, it has also been pointed out that this measurement of the flow and metabolism may not provide an accurate reflection of the observed phenomena because of the large difference (flow, 30 s; metabolism, 45 min) in the stable period over which each variable was measured [25]. It remains to be determined whether increases in ICP and CBV elicited by the stimulation in the present study are coupled to changes in metabolism. However. changes in ICP and CBV were observed soon after the beginning of the stimulation, and it is difficult to consider that changes of metabolism would occur within such a short time (within a few seconds) and immediately reflect the cerebral vessel response. It seems unlikely therefore that the responses elicited in this study were due to a change in metabolism. In the past, it was found that only an EEG arousal response produced by electrical stimulation of the brainstem was accompanied by an increase in cortical blood flow [9]. On the other hand, electrical stimulation of the dorsal medullary reticular formation, which produced an increase in CBF, did not alter the EEG [8]. Iadecola et al. [8] proposed that these conflicting observations might indicate the existence of two separate functional systems in the brainstem. In the present study, the arousal pattern was mostly observed in the central part of the pontine reticular formation, but scarcely in the dorsal meduUary reticular formation. Our results support the idea of Iadecola et al. It has been reported that the neurons of the rostral ventrolateral medullary reticular formation project into the intermediolateral column of the spinal cord and that this region is the origin of
163 s y m p a t h e t i c activities [24]. I n this region, t h e r e w e r e o n l y few sites of w h i c h electrical s t i m u l a t i o n y i e l d e d a n i n c r e a s e i n I C P i n cats w i t h s p i n a l i z a tion and vagotomy. The region does not therefore s e e m to b e r e l a t e d to t h e c e r e b r a l v a s o d i l a t a t i o n . On the other hand, the dorsal medullary reticular f o r m a t i o n is a p p a r e n t l y r e l a t e d to t h a t f u n c t i o n . These results imply that the brainstem reticular f o r m a t i o n in t h e a r t e r i a l p r e s s o r a r e a d o e s n o t c o n t r o l t h e c e r e b r a l v a s c u l a r t o n u s in a u n i f o r m fashion.
Acknowledgements T h e a u t h o r is g r a t e f u l to P r o f e s s o r S. M a t s u u r a a n d Dr. M. N a k a i for t h e i r critical r e a d i n g of t h e m a n u s c r i p t . H e also w i s h e s to t h a n k M e s s r s . T. K o n i s h i , T. K i t a n o , K. N i s h i m a k i a n d T. Yamamoto, medical students at Osaka City Univ e r s i t y M e d i c a l School, for t h e i r t e c h n i c a l assist a n c e . T h i s w o r k was s u p p o r t e d in p a r t b y a G r a n t - i n - A i d for Scientific R e s e a r c h f r o m t h e M i n i s t r y o f E d u c a t i o n , S c i e n c e a n d C u l t u r e of Japan.
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