ASCENDING CONDUCTION IN RETICULAR ACTI- VATING ..., Exams of Anatomy

Download ASCENDING CONDUCTION IN RETICULAR ACTI- VATING ... and more Exams Anatomy in PDF only on Docsity! Reprinted from I. hretrroplzysiol., 1951 41 : 461-477 ASCENDING CONDUCTION I N RETICULAR ACTI- VATING SYSTEM, WITH SPECIAL REFERENCE TO THE DIENCEPHALON T. E. C. W. TAYLOR' AND H. W. MAGOUNt Department of Anatomy, Northwestern University Medical School, f Chicago, Illinois (Received for publication December 26, 1950) RECENT study has revealed a cephalically directed brain stem system whose stimulation desynchronizes the electrical activity of the cerebral cortex in a manner simulating that observed in awakening from sleep or in the EEG arousal reaction (8). This system was found to be distributed in the reticular formation of the medulla, the tegmentum of the pons and midbrain and the sub- and hypothalamus. The means by which its activating influence became exerted upon the cortex was speculated upon and, because of the generalized distribution of the cortical effects, it seemed likely that the diffuse thalamic projection system was concerned. Some evidence favoring this possibility was obtained but the problem was left for further investigation. Following preliminary determination of the organization of the diffuse thalamic projection system (12), the present study has explored this matter further: (i) by determining the thalamic regions whose electrical activity is desynchronized by stimulation of the reticular formation of the lower brain stem, (ii) by determining the distribution of thalarnic sites from which evoked potentials are recorded upon single shock stimuli to the reticular activating system, (iii) by exploring the thalamic areas whose direct excita- tion desynchronizes the electrocorticogram, (iv) by ascertaining the distri- bution of cortical potentials evoked by single shock stimulation of the reticular activating system, and (v) by determining the effect of diencephalic lesions on ascending conduction of the reticular influence. The results indi- cate that the ventromedial part of the thalamus is most critically involved in transmission of the reticular activating influence, with the rest of the thalamus (including the diffuse thalamic projection system) playing a sub- sidiary role. Evidence, moreover, is provided that a proportion of the influ- ence of the reticular activating system upon the cortex may be exerted by an extra-thalamic route, paralleling that of the secondary response system described by Morison et al, (1, 10, 11). METHODS Cats immobilized with B-erythroidine were used, with a Palmer respirator providing artificial respiration. Exposures were made under local procaine. S m d doses of chloralo- -- * Department of Neurosurgery, University of Toronto. Medical Research Fellow, National Research Council, Canada. t Present address: Department of Anatomy, School of Medicine, University of Cali- fornia at Los Angeles. -- 462 T. E. STARZL, C. W. TAYLOR AND H. W. MAGOUN sane (5-7 mg./kg.) or nembutal (2-5 mg. /kg.) were employed to impart a degree of SJ n - chrony to the electrical activity of the brain. Deep pickup or stimulating electrodes \\ere oriented with a Horsley-Clarke instrument. Stimulating current, delivered with bipolar concentric electrodes, consisted of condenser discharges, usually with a ft~lling ph,lse of 0.5 msec., from a Goodwin stimulator. Subcortical activity was recorded with bipolar con- centric electrodes consisting of the exposed tips of an insulated stainless steel barrel con- taining an insulated copper wire, with a polar separation of 0.5-2.0 mm. Cortical tracings were taken with brass screw electrodes resting on dura, or with silver-balled, pial pickups oriented with a Grass multiple electrode carrier. A Grass amplifier with ink-writer was used for recording. RESULTS I . Subcortical desynchronization with high frequency bulbar stimulation. When the bulbar reticular formation was stimulated at 250/sec., usually with 2 volts, and recording electrodes moved systemically through the fore- brain, the degree of desynchronization of subcortical electrical activity FIG. 1. Transverse sections through hemisphere, showing regions exhibiting de- synchronization of electrical activity during high frequency stimulation of bulbar or mid- brain reticular formation (light shading), and evoked potentials on single shock reticular stimulation (dark shading). Note similarity of distribution. Abbreviations for Figs. 1, 4, 7 and 8 are as follows: A-amygdala, AC-anterior commissure, AM-anteromedial nuc., AV-anteroventral nuc., BIC-brachium of the inferior colliculus, BP-basis pedunculi, C--caudate nuc., CE-nuc. centralis medialis, CL---claustrum, CL-nuc. centralis lateralis, CM--centre median, F-fornix, GP-globus pallidus, H-habenular nuclei, HVM-hypothalamic ventromedial nuc., LA-nuc. lateralis anterior, LG-lateral genicu- late nuc., LP-nuc. lateralis posterior, M-medial nuc., MB-mammillary body, MG- medial geniculate nuc., ML-medid lemniscus, NR-red nuc., OC-optic chiasma, OT- optic tract, P-posterior nuc., PC-posterior commissure, PL-pulvinar, PRE-pretectal region, PT-putamen, RE-nuc. reunlens, S--septum, SC-superior colliculus, SG- suprageniculate nuc., S N s u b s t a n t i a nigra, SU-subthalamic nuc., RT-reticular nuc., VA-nuc. ventralis anterior, VL-nuc. ventralis lateralis, VM-ventromedial nuc.,VP- nuc. ventralis posterior, VPLLventroTosterolateral nuc., VPM-ventroposteromedial nuc., 21-zona incerta. RETICULAR ACTIVATING SYSTEM ;ifter cessation of the stimulus (Fig. 2B-D). Irregularly seen was an immedi- after-discharge consisting of fast, high amplitude waves. This last was noted when recording with concentric bipolar pickups (Fig. 2F), but was seen best with broader pickups (Fig. 3B-D). This exuberant after-discharge was found in the midbrain and diencephalic localities of acti- vation outlined above, but could not be followed into the capsule. I t was largest in the midbrain tegmentum and diminished progressively upon moving cephalad. Conversely, with midbrain reticular stimulation, a similar after-discharge was recorded from the bulbar reticular formation. FIG. 3. Records of activity between tips of electrodes placed 3 mm. apart and oriented medioleterally in deep structures, showing subcortical activation and after-discharge of large fast waves induced hy 2 V., 250/sec. stimulation of bulbar reticular formation marked by heavy line). I n each case electrodes are a t 1, 4, and 7 rnm. from midline. Areas include: (A) rostral portion of thalamus, with electrodes from medial to lateral in nuc. reuniens, reticular nuc., and internal capsule; (B) mid-thalamus, with electrodes in ventro- medial nuc., ventrolateral nuc., and ~entro~osterolateral nuc.; (C) rostral midbrain, with electrodes in central gray, midbrain tegmentum and substantia nigra; and (D) caudal midbrain, with electrodes in red nucleus, midbrain tegmentum, and substantia nigra. In designating channels, R 1-4 indicates recording to be between tips of electrodes placed at 1 and .t mm. from midline; R 4-7 between electrodes a t 4 and 7 mm. from midline; and 11 1 -7 bt.tween electrodes a t 1 and 7 mm. from midline. 2. Sztbcortical potentials evoked by single shock reticular stimulation. It was soon noticed that subcortical regions exhibiting desynchronization ilpon high frequency reticular stimulation also showed large potentials (either spikes or waves) when a single pulse was delivered to the bulbar or midbrain reticular formation. Distribution of the regions from which these evoked potentials could be recorded is shown by darker shading on the transverse sections through the forebrain in Figure 1. The areas of projec- tion closely parallel those for subcortical activation and include the teg- menturn, ventromedial thalamus (centromedian, ventromedial and ventro- 466 T. E. STARZL, C. W. TAYLOR AND H. W. MAGOUN lateral nuclei), sub- and hypothalamus and internal capsule. Occasional effects were sometimes seen in the dorsal thalamus (D, E), these invariably having a broad wave form and usually being evanescent. : Typical evoked potentials are seen in the left colunn of Figure 2, from the internal capsule (A), ventromedial thalamic nucleus iB), subthalamus (C, D), centre median (E), and the reticular formation of the midbrain (F). That these electrical alterations are dependent on the integrity of neural channels is shown by their disappearance, either upon death of the animal or by the interposition of a lesion between the stimulus and pickup. LAY Fic. 4. Transverse sections through hemisphere with shading indicating regions whose direct stimulation yields generalized cortical activation. More darkly shaded arens are thoze from which effect was most reliable and had lowest threshold. Note similar distribu- tion to that seen in Fig. 1. Such rostrally propagated reticular potentials recorded from the sub- thalamus are shown with different frequencies of stimulation (Fig. 2G): single shock, 20/sec., 50/sec. and 75/sec. Individual evoked potentials follow the stimulus with little diminution of amplitude until a frequency of 40-50/sec. is reached but, with higher stimulus rates, are submerged in the low fast discharge of activation. In the experiment from which this record was taken, as in all, the ventralis posterior and other sensory relay nuclei were also explored, but spikes were not found. It is not possible, therefore, to attribute these potentials to the inadvertent stimulation of lemniscal or other long afferent paths bordering the reticular formation. ‘The rostral passage of reticular influences can thus be traced with equiva- lent results, using for reference either the desynchronization caused by high frequency stimulation or the potential evoked by a single shock. The elec- trical alteration in ‘either case passes forward through the midbrain, sub- and hypothalamus, ventromedial part of the thalamus, and into the internal f RETICULAR ACTIVATING SYSTEM capsule. Moving dorsally in the thalamus, effects are increasingly harder to obtain and, similarly, upon pursuing the internal capsule forward, they wane progressively. 3. Activation of electrocorticogram by direct stimulation of brain stem. Stimuli were delivered a t 250 sec., usually with 2 volts, and electrocortico- grams taken from widely distributed cortical areas (Fig. 5). The generalized activation observed during stimulation of the reticular formation a t bulbar (Fig. 5A) and midbrain levels (B) is seen also during excitation of the ven- tromedial thalamus (C) and internal capsule (D), all parts of the cortex exhibiting change. Regions whose stimulation induced such generalized cortical desynchronization are shown with shading on transverse sections in Figure 4, with the most dependable foci more darkly shaded. In the midbrain, the tegmentum was broadly included in the inciting zone. Cortical activation was best upon stimulation of the medial mesencephalon, how- ever, in the same localities outlined for reticular spikes and subcortical activation (Fig. 4G, H). In addition. more lateral structures also yielded a generalized cortical effect. The ubiquitous cortical arousal elicited by excita- tion of this lateral zone was best when the afferent pathways present there- the brachium of the inferior colIiculus and the medial lemniscus-were stimulated. In these instances, however, the cortical projection areas of these pathways were often specifically affected. With stimulation of the medial lemniscus, for example, high amplitude fast waves were evoked in the sensory cortex, in addition to desynchronization of activity in other cortical areas (Fig. 5G), and similar effects in the auditory cortex were observed upon stimulation of the brachium of the inferior colliculus. At a thalamic level (Fig. 4C-F), general cortical arousal was best pro- duced by stimulation of the sub- and hypothalamus, and the ventromedial portion of the thalamus, including the ventromedial and most of the ventro- lateral nuclei, with a lateral excitable extension into the adjacent reticular nucleus and internal capsule. Stimulation of the diffusely projecting nuclei of the thalamus did not activate the cortex, except in the perimeter of the excitable zone just described and, of the relay nuclei, only the ventralis posterior appeared involved and then only in a marginal sense, along the fringes of the responsive area. At the cephalic pole of the thalamus, the lateral migration of the excit- able activating core was completed, and was predominantly capsular, with inclusion of the reticular nucleus and globus pallidus to a lesser extent. More rostrally still (Fig. 4A, B), the region is seen to continue forward in the internal capsule, which structure, rather than the basal ganglia (5), appears to be the excitable focus in this region. Although high frequency stimulation of the relay nuclei did not cause the generalized cortical de~ynchroniz~tion just described, a localized pro- vocation of fast activity was usually seen in their projection cortex. This effect was particularly clear in the case of the geniculate nuclei, which are far removed from the more medial regions that yield a generalized arousal. tentials could follow frequencies up to 8-10 'sec. as see11 in the ,~t~tcnos sigmoid (Fig. 6D). Moreover, the evoked potentials were routinely sh:lry>t.s and less wave-like than those recorded from the more caudal cort&;tl In Fig. 6B, D, and E the midbrain tegmentum was excited ill C the ~*%~*,$~,~;~$~;p~~~p~~~~,~~Jp~,,f~f)~~;.~,~~~fl::;~:.-~,'.. ~ ~ & # p & f f i V : h ~ , * . * J m . '. 1.1 '- f $ ~ ~ ! ~ ~ ~ ~ ~ / ; ~ l ~ { r ' i ; i ; ~ ~ ~ ~ ~ ~ p r ' L r \ ~ ; ~ > ~ : ~ ~ , ~ ~ A w : ; - ; : : ! & ~ , + ; ~ ? < ! 'aL~\//<u\h,'"V\pd$ J ,'bJ*d~/d\h~+%'L~L~<v~~, 3 1 . 1 Pm ~ + , ~ ~ ~ & i # $ ~ $ $ W $ ~ y ~ ; ~ R & i ' ' h , r ~ \ ' : : ,;4444w+ppp&~ I3 1 1 1 1 1 G & V P ~ ;iif r v c !Jp,:;.* iu , .,LC f rqyq4b8q \ I I li~/J(ur"Cb'u'~fiZ2SV~~'rl~~~ D FIG. 6. Records showing alterations in cortical electrical activity evoked by 2 -5 V. stimulation of activating system in midbrain or bulb (C). Pickups with bipolar concentric electrodes, with point in deeper layers of cortex or subjacent white matter and barrel on surface. Designation of channels indicate: A SIG-anterior sigmoid or motor, LAT ASSOC -lateral association, MID SUP-middle suprasylvian association, PRO-proreus or frontal association, P SIG-posterior sigmoid or sensory, VIS-visual. In (A) are shown the variable responses recorded from visual and lateral association areas initially (I-left) and after 90 sec. of intermittent stimulation (1-right). Potential changes induced by 25/sec. (2) and 250/sec. (3, 4) stimulation are also shown. Evoked potentials are shown in gyrus proreus (B); anterior sigmoid (C, D) with frequency of 7.5 sec. in D; posterior sigmoid (E); lateral association area fF); and middle suprasylvian association area ( G ) in which gradual increment of response occurred with continued stimulation. - RETICULAR ACTIVATING SYSTEM bulbar reticular formation. The most characteristic feature of more caudal cortical effects was their great variability and their ability to be augmented by serially repeated stimuli (Fig. 6A, G). - Thus the salient features of reticulocortical connections, as studied with single pulse stimuli either to the bulbar reticular formation or midbrain tegmentum, were the generality of effect upon the proper conditions, the predominance of effect in the rostra1 part of the cortex, and the ability of the cortex to be "conditioned" in the caudal regions where the potentials were 5. Effect of diencephalic lesions on activation elicited from lower brain stem. From the data presented, i t appeared that reticular influences might follow alternative ascending routes to the cortex (see Figs. 1, 4): (a) extrathalami- cally, directly into the internal capsule from the sub- and hypothalamus, and (b) thalamically, with the principal i d u x through its ventromedial portion. In order to determine the relative importance of these respective pathways, electrolytic lesions were made eliminating one or the other. First, the thalamus was destroyed, leaving the basal diencephalon and internal capsule intact (Fig. 7, 1-4). In the lesion shown, the thalamus was destroyed almost in its entirety, with only nuclear borders being spared. Although a portion of the centre median and the caudal part of the medial r~ucleus were not directly injured, all possible radiations lateralward and forward from them were severed (Fig. 7,3), indicating a complete functional thalarnic destruction. With such a lesion, the spontaneous electrocortico- gram showed almost no activity in the sensory-motor region and small fast discharge in the auditory area (Fig. 7A, top record). Stimulation either in the midbrain (A, top record, and B) or in the bulbar reticular formation (C) could still activate the cortex. The after-effect of stimulation differed, how- ever, from that observed in the intact animal. After high frequency stimu- lation of the activation system, large amplitude, fast frequency, recurring bursts frequently followed after some seconds' delay (Fig. 7A). Moreover, with the thalmus destroyed, single pulse stimuli to the tegmental or bulbar activating areas still evoked cortical potentials (Fig. 7B). An incidental finding in this case was the ease with which seizures could be provoked by brain stem stimulation. Although ordinarily 3 or 5 volt high frequency stimulation never initiated a cortical seizure, in this animal seizures occurred twice. In Figure 7E is seen the development and course of such a cortical fit, apparently provoked by midbrain tegmental stimulation at 5 volts, 250/sec. Next, since it appeared that activstion pathways partially followed an extrathalamic route, electrolytic lesions were produced in the lower part of the internal capsule, throughout the length of the diencephalon, by inserting the electrode from a lateral approach through the auditory cortex (Fig. 8, 1-4). This lesion destroyed extrathalamic pathways from the midbrain teg- mentum and sub- and hypothalamus to the internal capsule while sparing connections of these structures with the thalamus as well as leaving intact a good proportion of thalamocortical connections. Therefore, any desyn- 472 T. E. STARZL, C. W. TAYLOR AND H. JV. ~ I - A G O U S chronization of electrocortical activity, upon stimulation of ttle rericul.!r system in the lower brain stem of this preparation, might be to bC. nit,- diated through the thalamus. With such a lesion, spontaneous synchrony was a prominent fe,ttltrc of the electrocorticogram, with large recurrent 7-lO/sec. spilldle bursts domi- nating the picture, especially in the motor area (Fig. 8A). TI1is finding resem- bled that observed earlier upon elimination of the activation system at more caudal levels, and has been attributed to the release of synchronizing thIllarn- ic elements (particularly the recruiting system) from activating influences (6). In the instance shown in Figure 8, the medial geniculate bodies were inadvertently almost entirely destroyed. However, click stimuli were still capable of evoking cortical potentials. Although no evoked discharge oc- curred in the auditory cortex, waves appeared in the motor and sensory areas (Fig. 8B). The amplitude of these evoked potentials varied with their relation to spontaneous spindle bursts for during an interspindle pericd the effect was extremely small, while just before the occurrence of a burst, the potential was much more prominent (Fig. 8B) and, indeed, a t times appeared to initiate the spindle (see also 9) . Single shock or low frequency stimulation of the activation system was . likewise capable of evoking waves in the cortex. The strongest effects, as illustrated by stimulation of the midbrain tegmentum at 3,/sec. (Fig. 8C), were in the same cortical areas exhibiting responses to click stimuIi. Follow- ing the lesion shown in Figure 8, 1-4, high frequency stimulation of the bulbar or midbrain reticular formation was still fully capable of desynchro- nizing the electrocorticogram (Fig. 8D, E). There was, moreover, no regional specificity or effect, all areas recorded being desynchronized. It thus appears that the ascending reticular activating influence may follow alternative routes to the cortex and course both by an extrathalamic path from basal diencephalic structures directly into the internal capsule and, as is usually the case with corticipetal discharge, by relay through the thalamus. In the latter route, the core of the system is concentrated in the ventromedial portion of the thalamus axid probably fans in a diffuse manner FIG. 7. Transverse sections through diencephalon (I+), showing complete functional destruction of thalamus in preparation from which records A-E were obtained. Channels are designated as follows: AUD-auditory cortex, MOT-motor cortex, SEN-sensory cortex. SEN-MOT-sensory to motor cortex, SUB-subthalamus, VIS-MID ASS- visual to lateral association cortex. Records obtained after a lesion show: A: (upper strip), RETICULAR ACTIVATING SYSTEM FIG. 8. See opposite page for legend. 476 T. E. STARZL, C. W. TAYLOR A N D H. Ur. h ~ . i \ ( ; ~ v s It appears, then, that in thalamic mediation of the arousll reaction rc titular influences enter the ventromedial part of the thalamus nrltl arc co,l!- municated to dorsal and lateral thalamic structures in an increasinSIv dit'ftllcs L - brush. Ultimate effect on the cortex might occur simply througIl r;tdin- tions of the individual nuclei. Whatever the channel involved, desynch rani- zation of the spontaneous activity of its ventromedial regioll would appear to be the primary event in electrocortical activation exerted through the thalamus. The extrathalamic component of the ascending reticular system has been seen to migrate laterally from the sub- and hypothalamus into the internal capsule, with the principal departure at and above the mammillnry level. Unequivocal evidence for this route is provided by persistence of generalized cortical activation upon high frequency stimulation of the cauclal portion of the reticular system after destruction of the thalamus. From the data presented, i t is clear that the extrathalamic ascending pathway of the activa- tion system closely parallels that for the "secondary response," described in 1936 by Derbyshire et a1 (2) as a late cortical wave induced by sciatic stimdation under deep anesthesia. This secondary response was distributed widely and bilaterally in the cortex, and could only follow stimuli up to 3/sec. under deep barbiturate anesthesia (4). By means of lesions it was ' shown to be transmitted through the medial midbrain tegmentum and subthalamus to reach the cortex by an ill-defined extrathalamic route (1). I t persisted after section of the medial lemniscus and could be reproduced by direct stimulation of the midbrain and basal diencephalon (11). While the path of the secondary response has been regarded as purely extrathala- mic, the present study has shown that after low capsular lesions click stimuli or single shocks to the medial brain stem still evoked widely distributed cortical waves which were evidently mediated through the thalamus. It may be emphasized that, as with the reticular activating system, high frequency stimulation of sensory pathways in the brain stem also causes a generalized cortical arousal, but with the distribution of effects diminishing progressively as the brain stem is ascended until, with direct excitation of the thalamic relay nuclei, desynchronization of electrocortical activity is limited to the respective projection area. An explanation for this is offered by the results of recent study of collaterals from afferent somatic and audi- tory paths, in which an extensive brush of collateral connections has been found moving into the medial brain stem as far forward as the thalamus (13). Thus with stimulation of peripheral receptors, collateral afferent impulses feed into the activating system, functionally mobilizing it (8). That this may occur even a t a thalamic level is seen by the slight over-all cortical desynchronization sometimes encountered during direct stimulation of the relay nuclei of the thalamus. SUMMARY The ascending course of the reticular activating system has been investi- - gated in the brain stem of the cat, with special reference to conduction through the diencephalon. With repetitive stimulation of this system in the bulb or mid-brain, desynchronization of electrical activity has been observed in the sub- and hypothalamus, ventromedial thalamus and internal capsule. Potentials chronization of electrocortical actiqity, and single shock stimuli delivered to them evoke widely distributed cortical potentials. These results suggest that alternative routes are available for corti- 3. cipetal conduction of the reticular activating influence over: (i) a thalamic path involving transmission to the ventromedial part of the thalamus, with k relays to the cortex from the remainder of this structure; and (ii) an extra- thalamic path involving direct passage into the internal capsule from the I i sub- and hypothalamus. In agreement, after selective destruction of either f ! one of these routes, leaving the other intact, generalized desynchronization of electrocortical activity could still be elicited by lower brain stem stimu- 4 : I t ' - lation. I /' I , REFERENCES 1 a a 1 1. DEMPSEY, E. W., MORISON, R. S., AND MORISON, B. R. Some afferent diencephalic / "-i - 4 1 pathways related to cortical potentials in the cat. Amer. J. Physiol., 1941, 131: 718- 1 731. i f 2. DERBYSHIRE, A. S., REMPEL, B., FORBES, A., AND LAMBERT, E. F. Effects of anes- a: f thetics on action potentials in the cerebral cortex of the cat. Amer. J. Physiol., 1936, 116: 577-596. f 4. F ~ R B E S , A. AND MORISON, B. R. . Cortical response to sensory stimulation under ! 7. LINDSLEY, D. B., SCHREINER, L. H., KNOWLES, W. B., AND MAGOUN, H. W. Be- id. havioral and EEG changes following chronic brain stem lesions in the cat. EEG clin. i . - J~ gag f the EEG: EEG d i n . ~europhys io l . , 1949, 1 : 455-473. . " P 1950,Z: 29-31. 10. MORISON, R. S., DEMPSEY, E. W., AND MORISON, B. R. On the propagation of cer- 1 / t electrical stimulation of thibrain stem. Aner. J. Physiol., 1941, 131 : 732- of reticular formation of brain stern. J. Nertrophysiol., 1951, 14: 479-496.