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Cortical projections of ascending nonspecific systems
Physiology and Behavior, Vol. 8, pp. 269-277. Brain Research Pubhcations Inc., 1972. Printed in Great Britain
Cortical Projections of Ascending Nonspecific Systems ' D A V I D S. P H I L L I P S , D U A N E D. D E N N E Y
Departments of Medical Psychology and Psychiatry, University of Oregon Medical School, Portland, Oregon 97201, U.S.A. R I C H A R D T. R O B E R T S O N , L E S L I E H. H I C K S 2 A N D R I C H A R D F. T H O M P S O N
Department of Psychobiology, University of California, Irvine, Irvine, California 92664, U.S.A. (Received 23 July 1971)
PHILLIPS,D. S., D. D. DENNEY,R. T. ROBERTSON,L. H. HICKS AND R. F. THOMPSON. Corticalpro]ectionsof ascending nonspecificsystems. PHYSIOL.BEHAV. 8 (2) 269-277, 1972.--Areal dlsmbutions on cerebral cortex of several types of non specific actwity were compared in cat. Spontaneous spindle bursts in pentobarbital and cerveau isol6 preparauons, nonspecific cortical association responses evoked by peripheral stimuli in the chloralosed animal, and short latency cortical responses evoked by single shock stimulation of the midbrain reticular formation were all found to have essentmlly identical cortical distributions. These occurred in four major foci, two on the middle suprasylvlan gyrus, one on the anterior lateral gyrus, and one on pericruciate cortex surrounding the cruciate sulcus. Association responses
Cortex
Nonspecific systems
NUMEROUS lines of evidence implicate common subcortical systems in various types of nonspecific projections to cerebral cortex. Thus, the medial thalamic nuclei and the brainstem reticular formation appear to be involved in projection of nonspecific cortical association responses [1, 2, 3, 11, 14, 32] and in control of spontaneous cortical spindling activity [5, 15, 16, 21, 24, 31]. Although detailed mapping has not been done, many authors have noted that the spontaneous spindling activity characteristic of the barbitalized and the cerveau isol6 cat tends to be more pronounced in certain regions of the cerebral cortex, particularly in sensory-motor and posterior areas [5, 8, 9, 17, 21, 24, 27]. Evoked association responses to peripheral sensory stimulation in the chloralosed cat, also found in these general regions of cortex [3, 4, 14, 35], are nonspecific for different modalities of stimulation and are relatively sharply localized in four foci, two on the suprasylvian gyrus, one on the anterior lateral gyrus, and one on pericruiate cortex [34]. Evoked responses to direct electrical stimulation of the brainstem reticular formation have also been reported to occur in these general regions of cortex [10, 13, 20, 25]. The present study is an empirical investigation of the relative areal distributions on the cerebral cortex of evoked association responses, spontaneous spindling activity and responses evoked by single shock stimulation of the midbrain reticular formation in cat. The term nonspecific is somewhat ambiguous. It is used to indicate lack of modality specificity in topography of response for the cortical polysensory association evoked responses [34]. F o r cortical projections
Reticuloeomcal projecUons
Spindles
of reticular and medial thalamic systems, and certain categories of electrocortical activity, it has often been used to imply absence of focalized cortical topography. Results of the present experiments indicate that the latter usage, at least, may require modification. The term association, used to describe cortical polysensory responses in pericruciate and suprasylvian regions, was defined earlier in terms of response properties [34] and does not imply any relationship to thalamic association nuclei.
METHOD
Forty-four cats were used. Four different types of preparation were employed: pentobarbital (40mg/kg, IP), cerveau isol6, chloralose (70 mg/kg, IP) with subsequent administration of pentobarbital, and chloralose with subsequent brainstem transection to yield a cerveau lso16. The cerveau isol6 was prepared, using ether, by spatula transection under stereotaxic control at the level of the inferior colliculus following removal of the cerebellum. Body temperature was maintained at 38°C by a thermostatic heating system. The hemisphere, after exposure and removal of dura, was kept moist in a saline-soaked cotton chamber. A stainless steel recording electrode 0.3 mm in dia., insulated except at the tip, was mounted on a movable carrier fitted with rectangular coordinates calibrated in millimeter units. This assembly was mounted in a holder in which the animal's head was rigidly supported. F o r monopolar recording the indifferent electrode
1This work was supported by Research Scientist Award MH-06650 from the National Institute of Mental Health (RFT), research grant NS-07661 from the National Institutes of Health (RFT), predoctoral fellowship MH-42521 from the National Institute of Mental Health (RTR), and Biological Sciences Research Training Grant MH-11095 from the National Institute of Mental Health. ~Dr. Hicks collaborated on certain phases of the project while on leave from the Department of Psychology, Howard University. 269
270
PHILLIPS, DENNEY, ROBERTSON, HICKS AND ItII)MPSON
was clamped to subcutaneous tissue. Bipolar recording utilized a small Insulated penetrating steel needle inserted to a depth of 2 mm in cortex and an mmmediately adjacent 0 3 mm dia. steel surface electrode. A concentric bipolar electrode (tip separaUon 0.5 mm) was used for single shock (1-2.5V) stimulation of the midbram reticular formation. The opUmal placement of the stimulating electrode was determined by concomitant recordmg of the nonspecific evoked cortical association response and the nonspecific evoked reUcular response to peripheral stimuh. Amplitude correlations of the tx~o responses to a successwe sertes of stimuli are highly sigmficant in the chloralosed preparation, always ranging above +0.50 using the product moment correlation coeffioent [32]. In contrast, correlations between cortical associaUon responses and evoked activity m sensory pathways, and between evoked reticular responses and evoked responses m sensory pathways, do not differ slgmficantly from zero [32, 34] There appears to be an exact correspondence in the midbrain between the locus of maximum evoked nonspecific reticular responses to peripheral stimuli and the locus that when stmaulated yields the largest evoked potentials in cortical assocmtion areas (approximate stereotaxlc coordmates: frontal plane 2, lateral 2-3, horizontal --2.5 in the Jasper and AjmoneMarsan [22] atlas--see Fig. 8d). This region appears to be that occupied by the ascending fibers from the pontine grant-celled reticular formation [26]. The phenomena described here may well involve the axons of this system Evoked or spontaneous actwity was mapped m 1 mm steps. Spontaneous acUwty ~vas recorded with a Gllson model M5P or a Grass model 7 polygraph or with a Tektromx 502 oscdloscope, and evoked responses were recorded OScllloscopically. In preparing maps of the distribution of spontaneous spindling, activity was recorded for one minute at each electrode placement and the medmn amphtude spindle burst envelope used. Responswe regions were repeatedly checked during mapping to Insure stability of the preparation. Comparisons of evoked nonspeofic association responses and spindle bursts were made in the same animals by first mapping evoked responses to peripheral stlmuh using chloralose, and then either administering pentobarbltal or transectmg the bramstein to produce a spindling preparation. Comparisons of evoked responses to peripheral and reticular sUmuli employed the chloralosed preparation. Peripheral stimuh were free field square pulse chck, hght flash and single pulse shock to toepads of ~psilateral forepax~. RESULTS
Charactertstics of spindle bursts. In the present series of experiments two easily differentiated forms of spindle burst were seen, one having predominantly positive components and the other having predominantly negative components (cf, Fig. 1). Spencer and Brookhart [30] categorized individual spindle waves as Type I (Initial positivity followed by longer duration negativity), Type II (large initial negativity followed by a small positivlty), and mixed (complex waveform with initml positivity). They noted that most spindle bursts were mixtures of these types of waves, but that certain classes of combinations appeared to predominate. In our experiments the most prevalent type of spindle burst (mixed wave burst, Fig. 1) had both positive and negatwe components, the positive being of much larger amplitude than the negative. They appeared to consist primarily of mixed type and Type I spindle waves. The second and less frequent type (Type II
wave burst, Fig. l) had predominantly negative c/~mponent,~ with small positive components. They appeared to consxst primarily of Type II waves.
Type Tl"
. 5 Mv.
,
, I Sec.
FIG. 1. The two forms of spindle bursts observed m the present experiments. Mixed refers to predominant presence of mixed waves and Type II to predominance of Type II waves (see [30]). Positivity up in this and subsequent figures.
One pentobarbital preparation and one cerveau lsole preparation were selected at random for frequency counts of the two types of spindle bursts. In the pentobarbital preparation, 633 of the 676 spindle bursts recorded in the experiment were mixed wave type, the Type II wave bursts occurring only 6 . 8 ~ of the time. In the cerveau isol6 preparation, 688 of the 708 recorded spindle bursts were mixed wave type, the Type II wave bursts occurring only 2.9 ~o of the time. These are typical values for our series of experiments. The overwhelming preponderance of spontaneous spindle bursts is thus of the mixed wave type. Because of the infrequent occurrence of Type !I wave bursts, maps of the cortical distribution of spindle bursts were made only for the mixed wave type. Cortical distribution of spindle bursts. The corhcal distributions of median amplitude envelopes of spindle bursts are shown in Fig. 2 for the pentobarbital (2a) and unanesthetized cerveau isol~ (2b) preparations. In both preparations the distributions of maximum amplitude burst envelopes closely resemble the distributions of evoked cortical association responses on the middle suprasylvian gyrus ( A M S A and P M S A - - A n t e r i o r and Posterior Middle Suprasylvlan Areas), the anterior lateral gyrus ( A L A - Anterior Lateral Area), and on pericruciate cortex ( P C A - Pericruciate Area). The entire lateral surface of the hemisphere was mapped in each of these experiments; only those regions yielding substantial spindling activity are shown in the figures. The mixed wave type spindle burst envelopes shown in Fig. I were of low amplitude or absent in all primary sensory specific areas of the cortex, as indicated by the examples shown in primary auditory and somatosensory cortex in Fig. 2. Because of interanimal variations in exact location of foci of maximum response, it is necessary to map both nonspecific chloralose evoked responses and spindling activity in the same animal to test for identity of distribution. Results of such experiments are shown in Fig, 3. Association
NONSPECIFIC SYSTEMS AND CORTICAL PROJECTIONS
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.
.
.
.
.
FIG. 2. Cortical areal distributionsof median amplitude mixed wave spindle burst envelopes for the pentobarbital (a) and unanesthetizedcerveau isol6(b) preparations. Insert shows cortical areas mapped.
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FIG. 3. Comparison of cortical areal distributions of spontaneous mixed wave spindle burst envelopes and association responses. (A) Association responses in the chlol~losed animal and spindle bursts after administration of pentobarbitM were mapped for areas PCA and ALA as shown in insert. (B) Association responses before, and spindle bursts after, brainstem transection for areas AMSA and PMSA in the chloralosed preparation.
271
responses were first mapped in the chloralosed preparation; animals were then shifted to pentobarbital anesthetic over a period of 12 hr (Fig. 3a), or the brainstem transected (Fig. 3b) and the distributions of spontaneous spindling activity mapped in these regions. Distributions of both types of responses are essentially identical. Spindle bursts were not seen in the chloralosed animal, but appear shortly after brainstem transection, long before effects of chloralose have worn off (e.g., Fig. 3b). The cortical distribution of the predominantly negative Type II wave spindle bursts could not be ascertained with any great degree of reliability since the frequency of their occurrence in both pentobarbital and cerveau isol6 preparations was low (see above). In our series of experiments they were found only in two of the nonspecific spindle loci. In the pericruciate area (PCA) they most often occurred at the ventral and posterior borders of the area. In the anterior lateral area (ALA) they were found surrounding the ansate sulcus. Pure Type II wave spindle bursts were not seen on the suprasylvian gyrus. The typical spindle burst selected from each cortical point to construct the maps of Figs. 2 and 3 was the median amplitude burst from a one minute sample (cf, Method). Quantitative data showing means (~) and standard errors (s~) of spindle bursts in the various responswe fields are given in Table 1 for a pentobarbital preparation and a cerveau isol6 preparation. Amplitudes of the overall spindle burst envelopes were measured for ten successive bursts at the point of maximum activity in each of the four spindle foci and in primary auditory and visual areas. Mean responses for the spindle response areas are consistently very much larger than for the primary areas; response variability is relatively low. An analysis of variance and range test comparing means was completed on the data for each animal. The results of these analyses indicated that the mean response amphtudes in all four spindle fields were significantly larger than the means in primary areas at better than the 1 ~ level of significance. Thus, for a given preparation, mean spindle burst amplitudes were relatively stable and consistently very much larger in the nonspecific spindle regions. Spindle bursts from unresponsive regions of cortex were of extremely low amplitude or nonexistent and had correspondingly low variability (cf, Figs. 2 and 3). Temporal characteristics of spindle bursts. Correlations of occurrence and amplitude of association evoked responses are extremely high m all four cortical response foci in the chloralosed preparation [36]. If a related common system is responsible for spindling in all four cortical areas, the time of onset and temporal pattern of spindling activity ought to be essentially the same in all four nonspecific spindle response fields. General coincidence of occurrence of spindle bursts has been noted in many studies [21, 24]. In Fig. 4, paired tracings are taken from all possible combinations of spindle fields, and from these regions and primary sensory areas, in the cerveau isol6 preparation. Each pair of tracings was taken at a different time. The time of onset and general temporal pattern of mixed wave spindle bursts are essentially identical for all pairings of the four spindle response fields. The probability of such similar temporal distributions of spindle bursts by chance alone is extremely low. Comparisons of temporal distributions of spindling in the spindle fields and in primary auditory and visual cortical fields are shown in the right portion of Fig. 4. All primary sensory spindles are small or nonexistent (see below), but where they occur, the temporal distributions appear similar to those in the
272
PHILLIPS, DENNEY, ROBERTSON. HICKS AND [H()MPS()N
AmA
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FIG. 4. Paired ECG records from all combinations of nonspeclfiC spindle response fields and from these regions and primary sensory areas. Cortical areas designated: PMSA, Posterior Middle Suprasylvlan Area; AMSA, Anterior Middle Suprasylvian Area; ALA, Anterior Lateral Area; PCA, Perlcruclate Area; AI, Primary Auditory; VI, Primary Visual.
TABLE MEANS AND STANDARD
ERRORS,
1
I N ~ W , OF S P I N D L E B U R S T A M P L I T U D E S AUDITORY
IN THE SPINDLE FOCI AND IN THE PRIMARY
ALA
for each sample) PCA AMSA
(n =
VISUAL AND
AREAS
10
PMSA
VI
AI
Pentobarbltal
:~ sT
490 38
440 37
460 26
370 36
90 9
150 19
Cerveau isol~
:~ sR
620 56
690 99
760 75
770 35
240 45
170 23
nonspecific spindle fields. The essentially identical temporal distributions in all four spindle response areas of spindle bursts was true only for mixed wave spindle bursts. In contrast, Type II wave spindle bursts are seldom present in more than one area at any given time, and appear to have no correspondence of temporal distribution with either Type II wave or mixed wave spindle bursts in other areas. Spindle bursts in sensory cortex. Mixed wave spindle bursts in primary sensory areas of the cortex are either small or not present (Figs. 2, 3, and 4 and Table 1). In somatic sensory cortex, sizable spindle bursts were found only along the anterior border of somatic area I in a band lying between the cruciate sulcus and the post-cruciate dimple, where the pericruciate associat:on response field and the primary motor cortex overlap (Figs. 2 and 3). Comparisons of simultaneous monopolar and bipolar records taken from the pericruciate spindle area and from
auditory area I are shown in Fig. 5. The upper tracing for each represents monopolar recording (actually against a distant skin indifferent electrode), and the lower tracing represents bipolar recording between this surface electrode and a small penetrating electrode inserted oerpendicular to the cortical surface to a depth of 2 mm directly below the surface electrode. Spindle bursts from the pericruciate area were considerably larger when recorded bipolarly than when recorded monopolarly. The surface monopolarly recorded bursts in these records were of the same amplitude as those recorded prior to insertion of the penetrating electrode. Such monopolar vs. bipolar comparisons are shown for a number of different cortical regions in Fig. 6. Records from association areas (a, b, c) all yield markedly larger spindles in the bipolar (lower) traces. In all other areas the bipolar spindle bursts are either of the same low amplitude as the monopolar surface records, or even smaller in amplitude.
NONSPECIFIC SYSTEMS AND CORTICAL PROJECTIONS
273
Bofo¢o AmlkeOk
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After Anesthetic
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AI
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FIG. 5. Simultaneous surface monopolar and surface-depth bipolar records from pericrucmte spindle area and primary auditory
a! ea.
ALA
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FIG. 6. Simultaneous surface monopolar (upper traces) and surface-depth bipolar (lower traces) actiwty from several cortical areas.
The record from posterior SI [1] is particularly striking. Small but clear spindles are seen in the surface record; however, no spindles whatever are seen in the bipolar record. Monopolar surface and depth recordings taken from sensory cortices demonstrate that although primary evoked potentials show polarity reversal between surface and depth, spindles in these areas do not (see Fig. 7); the recorded spindles from surface and from depth are in phase. Further, when a local anesthetic is placed on the cortical surface, the evoked potentials are greatly attenuated while spindles are not. This contrasts with spindles recorded in association areas. Here, surface and depth records of spindles appear 180 ° out of phase, and when a small amount of local anesthetic is placed at the recording site, the spindles are essentially eliminated, leaving only very small, m-phase, spindles. Reversal of polarity between cortical surface and depth placements has been interpreted as evidence for the local generation of evoked potentials [23] and spindle bursts [30] and lack of this
PMSA
,~
I
100 MY
FIG. 7. Surface monopolar (lower traces) and depth monopolar (upper traces) records taken from association-spindle fields and from primary sensory regions. Left column shows evoked potentials and ECG tracings before, and fight column after, a drop of local anesthetic (procaine hydrochloride) was placed at the recording site. Sweep duration for evoked potentials--100 msec; for ECG-1 sec.
reversal may mean that the potentials recorded are the result of volume conduction from other areas [34]. These data, showing that the in-phase spindles in sensory cortex are not eliminated by topical local anesthetic, are consistent with this interpretation. Thus, when mixed wave spindle bursts do occur in sensory regions of the cortex, they may not be locally generated. The lack of spindle activity in primary sensory cortex seems not to be due to the suppression of spontaneous rhythms in the thalamic relay nuclei by afferent stimulation. Spindling was not observed in primary auditory or somesthetic cortices in the cerveau isol6 preparation, and records of spontaneous activity in visual cortex showed no evidence of spindling, whether the animal was in a normally lighted or almost completely darkened room. Nor can the absence of spindling be attributed to a physiological unresponsive cortex. Normally-appearing evoked potentials, showing polarity reversals with depth, were observed in all primary areas. Cortical distributionof reticular evokedresponses. Beginmng with the classical observations of Moruzzi and Magoun [25], several authors have noted that cortical responses to reticular stimulation tend to be more evident in certain regions of cortex, particularly sensory-motor and posterior areas [10, 13, 20]. In the present experiments the detailed cortical distribution of responses evoked by single shock stimulation of the midbrain reticular formation was compared with the cortical distribution of nonspecific association responses evoked by peripheral stimuli in the chloralosed preparation. The stimulating electrode was placed in the region of the tegmentum yielding maximum evoked reticular responses
274
PHILLIPS, DENNEY, ROBERTSON, HICKS AND I HOMPSON
A
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MESENCEPHALICRETICULARFORMATION MESENCEPHALIC RETICULAR
FORMATION I .5 mV
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LIGHT FLASH
Q
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~
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MESENCEPHALICRETICULARFORMATION
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FIG. 8. Cortical dtstributlons of evoked responses to mesencephalic reticular single pulse electrical stimulation and association responses to peripheral stimuli. (A) Area PCA, (B) ALA, (C) AMSA and PMSA, and (D) photomicrograph showing placement of stimulating electrode.
to peripheral stimulation (cf, Method). The cortical distribution of short latency (4-7 msec) responses to reticular stimulation and association responses to peripheral stimuli are compared in Fig. 8. The distributions of responses are essentially identical. If the stimulating electrode in reticular formation is moved from the locus of maximum reticular responses, the relative amplitude distribution of cortical responses to reticular stimulation does not change, but absolute amplitudes of cortical responses decrease. Under conditions of our experiments we were never able to evoke any measurable responses in primary auditory, visual and somatic sensory areas of the cortex by single shock stimulation of the reticular formation. Buser and Borenstein [13] reported that repetitive electrical
stimulation of the midbrain reticular formation abolished cortical association responses to peripheral stimulation. We completed a recovery cycle analysis comparing responses evoked in cortex by single reticular shocks and peripheral stimuli. As shown in Fig. 9, the form of the interaction between reticular stimulus and peripheral stimuli does not appear to differ from the interaction between various peripheral stimuli. DISCUSSION
The results of these experiments indicate that the foci of maximum amplitude mixed wave spindle bursts on the cortex of the barbitalized or cerveau isol6 cat appear to correspond
NONSPECIFIC SYSTEMS AND CORTICAL PROJECTIONS % I00
¢ ~eo
q= -~. 60
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.~o
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Ret - Ipsdoterol
o 011
0-12
014
T~me Between
0i6
018
Shmuh (Sec)
FIG. 9. Recovery cycles of cortical association responses to peripheral stimuli and to mesencephalic reticular single pulse electrical stimulation. Relative response amplitude to the second of two stimuh as plotted as a function of time between stimuli.
exactly in location with the foci of maximum amplitude nonspecific association responses to peripheral sensory stimulation and foci of maximum amplitude short latency responses to electrical stimulation of the midbrain reticular formation in the chloralosed cat. There are thus four restricted areas of maximum mixed wave spindle bursts, two on the suprasylvian gyrus, one on the anterior lateral gyrus, and one on pericruciate cortex overlapping the dorsal portion of the primary motor cortex. There are no appreciable differences in cortical distribution of spindle bursts between the pentobarbital and cerveau isol6 preparations, although spindle activity is often somewhat more pronounced in the latter preparation. The onset times and temporal distributions of mixed wave spindle bursts are identical in all four cortical foci of maximum response. These results are all consistent with the hypothesis that spindle bursts and evoked association responses share a common cortical projection system. Spencer and Brookhart [29, 30] analyzed the intracortical distribution of spontaneous spindle waves in terms of the intcacortical patterns of augmenting and recruiting responses. They concluded that all spindle waves could be classified as being like augmenting waves (Type I), or like recruiting waves (Type II), or a combination of these (mixed type). Our classification of spindle bursts was based on their analysis. Two basic surface configurations of spindle bursts were seen in our experiments, a predominantly positive type (mixed wave) and a predominantly negative type (Type II wave). About 95 ~ of the spindle burst activity in our experiments was of the mixed wave type. Pure Type II wave spindles were seen only about 5 ~o of the time and only on the anterior border of the anterior lateral response focus and the posterior and ventral borders of the pericruciate response focus (i.e., primarily in somatic sensory area I). Onset t~mes and temporal distributions of Type II wave spindle bursts in these areas do not correspond to mixed wave bursts in any of the spindle response areas or to each other in the two anterior response areas. These findings provide further evidence for the necessity of a categorization scheme such as that developed by Spencer and Brookhart. Mixed wave spindle burst activity in primary sensory areas of the cortex was limited to regions bordering the nonspecific spindle response foci in our experiments. In somatic sensory area I spindle bursts were sizeable only along the anterior border where the pericruclate spindle response field overlaps. This pericruciate field is not coextensive with the primary
275 motor cortex either, overlapping only the dorsal portion dorsomedial to the coronal sulcus, and extending anterior to motor cortex. Thus the pericruciate spindle focus by no means corresponds to sensory-motor cortex, a portion of motor cortex and the bulk of somatic sensory area I exhibiting either very low amplitude spindle bursts or no measurable spindles. Spindle burst activity in auditory and visual areas was limited to regions bordering the suprasylvian gyrus. In primary sensory areas of the cortex, bipolar recording across the cortex yielded lower amplitude spindle bursts than did monopolar surface recording, and closer analysis indicated the records taken from surface and from depth were in phase. Bipolar recordings taken in the pericruciate and posterior association spindle response fields, in contrast, gave substantially larger spindle bursts than did surface monopolar recordings, and the surface and depth records were out of phase. Further, local anesthetic applied to the cortex eliminates spindles in the association areas, but not in primary sensory areas. These data suggest that mixed wave spindle burst activity recorded by surface electrodes on sensory cortex is not generated intracortically at the recording sites, at least under the conditions of our experiments, in contrast to spindle activity in association response foci. Although the relations between spindle bursts and recruiting responses are still not completely understood, these data may reopen the issue concerning the existence of recruiting in primary sensory cortex [19, 31]. It must be emphasized that our analysis is limited to the mixed wave spindle bursts, by far the most frequently occurring type, in which Spencer and Brookhart [30] Type I and mixed waves predominate. These resemble what Andersen and Andersson [5] term compound spindles, which they report as occurring simultaneously over widespread cortical areas. They also describe local spindles, occurring without concomitant spindle activity in other areas, that are similar to the infrequently occurring Type II wave spindles described here. These local spindles, generated in specific sensory thalamic nuclei and corresponding cortical areas [5, 6] appear to be mediated by different thalamo-cortical systems than the predominant mixed wave spindles we have studied here. Our findings on the cortical distribution and occurrence of mixed spindles may be interpreted in terms of a unitary pacemaker with at least principal projections to the four association areas. This is consistent with other studies showing abolition of cortical spindling and recruiting by lesions in the rostral pole of the thalamus [15, 18, 28, 38], and by lesions in the inferior thalamic peduncle [28]. The identity of cortical distributions of short latency responses to single shock stimulation of the midbrain reticular formation and longer latency association responses to peripheral stimulation, the similar recovery cycle function obtained for reticular and peripheral stimuli, and the identical cortical distribution of mixed spindle bursts would all seem to suggest a common system. However, Blgnall's [7] report that large lesions in the medial thalamus and rostral midbrain reticular formation do not eliminate cortical association responses raises some question as to what the system may be. Although the preponderance of evidence implicates the reticular formation and medial thalamic nuclei in the cortical association response [1, 2, 3, 11, 14, 32, 34], the possibility of multiple parallel inputs to the association areas has also been suggested [12]. The well localized distribution of mixed wave spindle activity described here may have implications for the function
276
PHILLIPS, DENNEY, ROBERTSON, HICKS AND THOMPSON
of these cortical regions in the behavmg ammal. The transition from cortical spindle activity to a desynchronized E E G has c o m m o n l y been used as an indicant of an aroused or attentive a m m a l [5, 24]. Since spindle activity occurs predominantly in the four association response foci, it follows that these are the cortical regions which would most clearly or reliably display desynchronization. Thus, the greatest differences in cortical activity between a drowsy animal and an attentive
or aroused one may occur In the association response legions These areas may thus be intimately involved in general arousal or attentive processes. The observations that evoked responses to reticular formation stimulation also occur only in these cortical regions, and other studies demonstrating an increase in unit activity in association response areas during periods of behavioral orienting [33], offer further support for this view.
REFERENCES
1. Albe-Fessard, D., D. Bowsher and A. Mallart. R6ponses 6voqu~es dans la formation r6ticul6e bulbaire au niveau du noyau giganto cellularis d'OlzewskL R61e de ce noyau dans la transmission vers le centre m6dlan du thalamus des afferences somatiques. J. Physiol. (Paris) 54: 271, 1962. 2. Albe-Fessard, D. and A. Fessard. Thalamic integrations and their consequences at the telencephahc level. In: Progress in Brain Research, edited by G. Moruzz~, et al. Vol. I, Brain Mechanisms. Amsterdam: Elsevier, 1963, 115-148. 3. Albe-Fessard, D. and A. Rougeul. Activit6s d'origine, somesth~slque 6voqu6es sur le cortex non-sp~cifique du chat anesth6sl6 au chloralose: r61e du centre m6dian du thalamus. Electroenceph. clin. Neurophysiol. 10: 131-151, 1958. 4. Amassian, V. E. Studies on organization of a somesthet~c association area, including a single umt analysis. J. Neurophysiol. 17: 39-58, 1954. 5. Andersen, P. and S. A. Andersson. Physiological Basis of the Alpha Rhythm. New York: Appleton, Century, Crofts, 1968. 6. Andersen, P., S. A. Andersson and T. Lomo. Nature of thalamocortical relations during spontaneous barbiturate spindle actiwty. J. Physiol. 192: 283-307, 1967. 7. Btgnall, K. E. Effects of subcortical ablations on polysensory cortical responses and interactions in the cat. Expl Neurol. 18: 56-67, 1967. 8. Bremer, F. Cerveau 'hsol6" et physiologie du sommeil. C.R. Soc. Biol. Paris 118: 1235-1241, 1935. 9. Brookhart, J. M. and A. Zanchetti. The relation between electrocortical waves and responsiveness of the corticospmal system. Electroenceph. clin. Neurophysiol. 8:427 ~a,4, 1956. 10. Bruner, J. Affer6nces vlsuelles non-primalres vers le cortex ~r6bral chez le chat. J. Physiol. (Paris) 57: Suppl. 12, 1-120, 1965. 11. Buser, P. Subcorhcal controls of pyramidal acUvlty. In" The Thalamus, edited by D. P. Purpura and M. D. Yahr. New York: Columbia University Press, 323-344, 1966. 12. Buser, P. and K. E. Bignall. Nonprimary projections on the cat neocortex. Int. rev. Neurobtol. 10: 111-t65, 1967. 13. Buser, P. and P. Borenstein. Suppression 61ective des r6ponses "associatives" par stimulation r6ticulaire chez le chat sous anesth6sie profonde au chloralose. J. Physiol. (Paris) 49: 86-89, 1957. 14. Buser, P., P. Borenstein and J. Bruner. Etude des syst~mes "assoclatifs" visuels et auditifs chez le chat anesth6si6 au chloralose. Electroenceph. clin. Neurophysiol. 11: 305-324, 1959. 15. Chow, K. L., W. C. Dement and S. A. Mitchel. Effects of lesions of the rostral thalamus on brain waves and behavior in cats. Electroenceph. clin. Neurophysiol. 11: 107-120, 1959. 16. Dempsey, E. W. and R. S. Morison. The interaction of certain spontaneous and induced cortical potentials. Am. J. Physiol. 135: 301-308, 1942. 17. Derbyshire, A. J., B. Rempel, A. Forbes and E. E. Lambert. The effects of anesthetics on action potentials in the cerebral cortex of the cat. Am. J. Physiol. 116: 577-596, 1936. 18. Hanberry, J., C. Ajmone-Marsan and M. Dilworth. Pathways of nonspecific thalamo-cortical projection system. Electroenceph, clin. Neurophysiol. 6: 103-118, 1954.
19. Hanberry, J. and H. Jasper. Independence of diffuse thalamocortical projection system shown by specific nuclear destruction. J. Neurophysiol. 16: 252-271, 1953. 20. Ilyutchenok, R. Y. and V. S. Zmevich. Short latency reticulocortical potentials: Effect of muscarinic anticholinerglc drugs. Neuropharmacology 9: 433 a.~9, 1970. 21. Jasper, H. H. Unspecific thalamocortical relations in: Handbook ofPhyswlogy, Neurophysiology, edited by J. Field, H. W. Magoun and V. E. Hall. Vol. 2. Washington, D.C.American Physiological Society, 1307-1322, 1960. 22. Jasper, H. H. and C. Ajmone-Marsan. A Stereotaxw Atla~ oJ the Diencephalon of the Cat. Ottawa" National Research Council of Canada, 1954. 23. L1, C. L., C. Cullen and H. Jasper. Laminar mlcroelectrode studies of specific somato-sensory cortical potentials. J. Neurophysiol. 19: 111-136, 1956. 24. Lindsley, D. B. Attention, consciousness, sleep and wakefulness. In: Handbook of Physiology, Neurophysiology, Vol. 3, edited by J. Field, H. W. Magoun and V. E. Hall. Washington D.C.: American Physiological Society, 1553-1593, 1960. 25. Moruzzi, G. and H. W. Magoun. Brainstem reticular formation and activation of the EEG. Electroenceph. clin. Neurophysiof. 1: 455473, 1949. 26. Nauta, W. J. H. and H. G. J. M. Kuypers. Some ascending pathways in the bramstem reticular formation. In: Reticular formation of the brain, edited by H. H. Jasper, et al. Boston: Little, Brown, 1958, pp. 3-30. 27. Ralston, B. and C. Ajmone-Marsan. Thalamlc control of certain normal and abnormal cortical rhythms. Electroenceph clin. Neurophysiol. 8: 559-582, 1956. 28. Skinner, J. E. and D. B. Lindsley. ElectrophyslologJcal and behavioral effects of blockade of the nonspeclfic thalamocortical system. Brain Res. 6:95-118, 1967. 29. Spencer, W. A. and J. M. Brookhart. Electrical patterns of augmenting and recrmting waves in depths of sensorimotor cortex of cat. J, Neurophysiol. 24: 26-49, 1961. 30. Spencer, W. A. and J. M. Brookhart. A study of spontaneous spindle waves in sensonmotor cortex of cat. J. Neurophysiol. 24: 50-65, 1961. 31. Starzl, T. E. and H. W. Magoun. Organization of the diffuse thalamlc projection system. J.Neurophysiol. 14: 133-146, 1951. 32. Thompson, R. F. Thalamocortical orgamzatlon of association responses to auditory, tactile, and visual stimuli in cat. Proc. X X l l lnt. Congr. Physiol. Sci. Leiden. 48: 1057, 1962. 33. Thompson, R. F., L. A. Bettinger, H. Birch, P. M. Groves and K. S. Mayers. The role of synaptm inhibitory mechamsms In neuropsychological systems. Neuropsychologia 7: 217-234, 1969. 34. Thompson, R. F., R. H. Johnson and J. Hoopes. Organization of auditory, somatic sensory and visual projections toassociation fields of cerebral cortex in the cat. J.Neurophysiol. 26: 343-363, 1963. 35. Thompson, R. F. and R. M. Sindberg. Auditory response fields in association and motor cortex of cat. J. Neurophyswl. 23: 87-105, 1960. 36. Thompson, R. F., H. E. Smith and D. Bhss. Auditory, somatic sensory and visual response interactions and mterrelauons Jn association and primary cortical fields of the cat. J Neurophysiol. 26: 365-378, 1963.
NONSPECIFIC SYSTEMS AND CORTICAL PROJECTIONS
277
37. Velasco, M. and D. B. Lindsley. Role of orbital cortex in regulation of thalamocortical activity. Science 149: 1375-1377, 1965.
38. Weinberger, N. M., M. Velasco and D. B. Lindsley. Effects of lesions upon thalamically induced electrocortical desynchronization and recruiting. Electroenceph. clin. Neurophysiol. 18: 369-377, 1965.
Cortical Projections of Ascending Nonspecific Systems ' D A V I D S. P H I L L I P S , D U A N E D. D E N N E Y
Departments of Medical Psychology and Psychiatry, University of Oregon Medical School, Portland, Oregon 97201, U.S.A. R I C H A R D T. R O B E R T S O N , L E S L I E H. H I C K S 2 A N D R I C H A R D F. T H O M P S O N
Department of Psychobiology, University of California, Irvine, Irvine, California 92664, U.S.A. (Received 23 July 1971)
PHILLIPS,D. S., D. D. DENNEY,R. T. ROBERTSON,L. H. HICKS AND R. F. THOMPSON. Corticalpro]ectionsof ascending nonspecificsystems. PHYSIOL.BEHAV. 8 (2) 269-277, 1972.--Areal dlsmbutions on cerebral cortex of several types of non specific actwity were compared in cat. Spontaneous spindle bursts in pentobarbital and cerveau isol6 preparauons, nonspecific cortical association responses evoked by peripheral stimuli in the chloralosed animal, and short latency cortical responses evoked by single shock stimulation of the midbrain reticular formation were all found to have essentmlly identical cortical distributions. These occurred in four major foci, two on the middle suprasylvlan gyrus, one on the anterior lateral gyrus, and one on pericruciate cortex surrounding the cruciate sulcus. Association responses
Cortex
Nonspecific systems
NUMEROUS lines of evidence implicate common subcortical systems in various types of nonspecific projections to cerebral cortex. Thus, the medial thalamic nuclei and the brainstem reticular formation appear to be involved in projection of nonspecific cortical association responses [1, 2, 3, 11, 14, 32] and in control of spontaneous cortical spindling activity [5, 15, 16, 21, 24, 31]. Although detailed mapping has not been done, many authors have noted that the spontaneous spindling activity characteristic of the barbitalized and the cerveau isol6 cat tends to be more pronounced in certain regions of the cerebral cortex, particularly in sensory-motor and posterior areas [5, 8, 9, 17, 21, 24, 27]. Evoked association responses to peripheral sensory stimulation in the chloralosed cat, also found in these general regions of cortex [3, 4, 14, 35], are nonspecific for different modalities of stimulation and are relatively sharply localized in four foci, two on the suprasylvian gyrus, one on the anterior lateral gyrus, and one on pericruiate cortex [34]. Evoked responses to direct electrical stimulation of the brainstem reticular formation have also been reported to occur in these general regions of cortex [10, 13, 20, 25]. The present study is an empirical investigation of the relative areal distributions on the cerebral cortex of evoked association responses, spontaneous spindling activity and responses evoked by single shock stimulation of the midbrain reticular formation in cat. The term nonspecific is somewhat ambiguous. It is used to indicate lack of modality specificity in topography of response for the cortical polysensory association evoked responses [34]. F o r cortical projections
Reticuloeomcal projecUons
Spindles
of reticular and medial thalamic systems, and certain categories of electrocortical activity, it has often been used to imply absence of focalized cortical topography. Results of the present experiments indicate that the latter usage, at least, may require modification. The term association, used to describe cortical polysensory responses in pericruciate and suprasylvian regions, was defined earlier in terms of response properties [34] and does not imply any relationship to thalamic association nuclei.
METHOD
Forty-four cats were used. Four different types of preparation were employed: pentobarbital (40mg/kg, IP), cerveau isol6, chloralose (70 mg/kg, IP) with subsequent administration of pentobarbital, and chloralose with subsequent brainstem transection to yield a cerveau lso16. The cerveau isol6 was prepared, using ether, by spatula transection under stereotaxic control at the level of the inferior colliculus following removal of the cerebellum. Body temperature was maintained at 38°C by a thermostatic heating system. The hemisphere, after exposure and removal of dura, was kept moist in a saline-soaked cotton chamber. A stainless steel recording electrode 0.3 mm in dia., insulated except at the tip, was mounted on a movable carrier fitted with rectangular coordinates calibrated in millimeter units. This assembly was mounted in a holder in which the animal's head was rigidly supported. F o r monopolar recording the indifferent electrode
1This work was supported by Research Scientist Award MH-06650 from the National Institute of Mental Health (RFT), research grant NS-07661 from the National Institutes of Health (RFT), predoctoral fellowship MH-42521 from the National Institute of Mental Health (RTR), and Biological Sciences Research Training Grant MH-11095 from the National Institute of Mental Health. ~Dr. Hicks collaborated on certain phases of the project while on leave from the Department of Psychology, Howard University. 269
270
PHILLIPS, DENNEY, ROBERTSON, HICKS AND ItII)MPSON
was clamped to subcutaneous tissue. Bipolar recording utilized a small Insulated penetrating steel needle inserted to a depth of 2 mm in cortex and an mmmediately adjacent 0 3 mm dia. steel surface electrode. A concentric bipolar electrode (tip separaUon 0.5 mm) was used for single shock (1-2.5V) stimulation of the midbram reticular formation. The opUmal placement of the stimulating electrode was determined by concomitant recordmg of the nonspecific evoked cortical association response and the nonspecific evoked reUcular response to peripheral stimuh. Amplitude correlations of the tx~o responses to a successwe sertes of stimuli are highly sigmficant in the chloralosed preparation, always ranging above +0.50 using the product moment correlation coeffioent [32]. In contrast, correlations between cortical associaUon responses and evoked activity m sensory pathways, and between evoked reticular responses and evoked responses m sensory pathways, do not differ slgmficantly from zero [32, 34] There appears to be an exact correspondence in the midbrain between the locus of maximum evoked nonspecific reticular responses to peripheral stimuli and the locus that when stmaulated yields the largest evoked potentials in cortical assocmtion areas (approximate stereotaxlc coordmates: frontal plane 2, lateral 2-3, horizontal --2.5 in the Jasper and AjmoneMarsan [22] atlas--see Fig. 8d). This region appears to be that occupied by the ascending fibers from the pontine grant-celled reticular formation [26]. The phenomena described here may well involve the axons of this system Evoked or spontaneous actwity was mapped m 1 mm steps. Spontaneous acUwty ~vas recorded with a Gllson model M5P or a Grass model 7 polygraph or with a Tektromx 502 oscdloscope, and evoked responses were recorded OScllloscopically. In preparing maps of the distribution of spontaneous spindling, activity was recorded for one minute at each electrode placement and the medmn amphtude spindle burst envelope used. Responswe regions were repeatedly checked during mapping to Insure stability of the preparation. Comparisons of evoked nonspeofic association responses and spindle bursts were made in the same animals by first mapping evoked responses to peripheral stlmuh using chloralose, and then either administering pentobarbltal or transectmg the bramstein to produce a spindling preparation. Comparisons of evoked responses to peripheral and reticular sUmuli employed the chloralosed preparation. Peripheral stimuh were free field square pulse chck, hght flash and single pulse shock to toepads of ~psilateral forepax~. RESULTS
Charactertstics of spindle bursts. In the present series of experiments two easily differentiated forms of spindle burst were seen, one having predominantly positive components and the other having predominantly negative components (cf, Fig. 1). Spencer and Brookhart [30] categorized individual spindle waves as Type I (Initial positivity followed by longer duration negativity), Type II (large initial negativity followed by a small positivlty), and mixed (complex waveform with initml positivity). They noted that most spindle bursts were mixtures of these types of waves, but that certain classes of combinations appeared to predominate. In our experiments the most prevalent type of spindle burst (mixed wave burst, Fig. 1) had both positive and negatwe components, the positive being of much larger amplitude than the negative. They appeared to consist primarily of mixed type and Type I spindle waves. The second and less frequent type (Type II
wave burst, Fig. l) had predominantly negative c/~mponent,~ with small positive components. They appeared to consxst primarily of Type II waves.
Type Tl"
. 5 Mv.
,
, I Sec.
FIG. 1. The two forms of spindle bursts observed m the present experiments. Mixed refers to predominant presence of mixed waves and Type II to predominance of Type II waves (see [30]). Positivity up in this and subsequent figures.
One pentobarbital preparation and one cerveau lsole preparation were selected at random for frequency counts of the two types of spindle bursts. In the pentobarbital preparation, 633 of the 676 spindle bursts recorded in the experiment were mixed wave type, the Type II wave bursts occurring only 6 . 8 ~ of the time. In the cerveau isol6 preparation, 688 of the 708 recorded spindle bursts were mixed wave type, the Type II wave bursts occurring only 2.9 ~o of the time. These are typical values for our series of experiments. The overwhelming preponderance of spontaneous spindle bursts is thus of the mixed wave type. Because of the infrequent occurrence of Type !I wave bursts, maps of the cortical distribution of spindle bursts were made only for the mixed wave type. Cortical distribution of spindle bursts. The corhcal distributions of median amplitude envelopes of spindle bursts are shown in Fig. 2 for the pentobarbital (2a) and unanesthetized cerveau isol~ (2b) preparations. In both preparations the distributions of maximum amplitude burst envelopes closely resemble the distributions of evoked cortical association responses on the middle suprasylvian gyrus ( A M S A and P M S A - - A n t e r i o r and Posterior Middle Suprasylvlan Areas), the anterior lateral gyrus ( A L A - Anterior Lateral Area), and on pericruciate cortex ( P C A - Pericruciate Area). The entire lateral surface of the hemisphere was mapped in each of these experiments; only those regions yielding substantial spindling activity are shown in the figures. The mixed wave type spindle burst envelopes shown in Fig. I were of low amplitude or absent in all primary sensory specific areas of the cortex, as indicated by the examples shown in primary auditory and somatosensory cortex in Fig. 2. Because of interanimal variations in exact location of foci of maximum response, it is necessary to map both nonspecific chloralose evoked responses and spindling activity in the same animal to test for identity of distribution. Results of such experiments are shown in Fig, 3. Association
NONSPECIFIC SYSTEMS AND CORTICAL PROJECTIONS
IMv~ 2 SEC
2b -
.
.
.
.
.
FIG. 2. Cortical areal distributionsof median amplitude mixed wave spindle burst envelopes for the pentobarbital (a) and unanesthetizedcerveau isol6(b) preparations. Insert shows cortical areas mapped.
A
"
\
1" I M V
FIG. 3. Comparison of cortical areal distributions of spontaneous mixed wave spindle burst envelopes and association responses. (A) Association responses in the chlol~losed animal and spindle bursts after administration of pentobarbitM were mapped for areas PCA and ALA as shown in insert. (B) Association responses before, and spindle bursts after, brainstem transection for areas AMSA and PMSA in the chloralosed preparation.
271
responses were first mapped in the chloralosed preparation; animals were then shifted to pentobarbital anesthetic over a period of 12 hr (Fig. 3a), or the brainstem transected (Fig. 3b) and the distributions of spontaneous spindling activity mapped in these regions. Distributions of both types of responses are essentially identical. Spindle bursts were not seen in the chloralosed animal, but appear shortly after brainstem transection, long before effects of chloralose have worn off (e.g., Fig. 3b). The cortical distribution of the predominantly negative Type II wave spindle bursts could not be ascertained with any great degree of reliability since the frequency of their occurrence in both pentobarbital and cerveau isol6 preparations was low (see above). In our series of experiments they were found only in two of the nonspecific spindle loci. In the pericruciate area (PCA) they most often occurred at the ventral and posterior borders of the area. In the anterior lateral area (ALA) they were found surrounding the ansate sulcus. Pure Type II wave spindle bursts were not seen on the suprasylvian gyrus. The typical spindle burst selected from each cortical point to construct the maps of Figs. 2 and 3 was the median amplitude burst from a one minute sample (cf, Method). Quantitative data showing means (~) and standard errors (s~) of spindle bursts in the various responswe fields are given in Table 1 for a pentobarbital preparation and a cerveau isol6 preparation. Amplitudes of the overall spindle burst envelopes were measured for ten successive bursts at the point of maximum activity in each of the four spindle foci and in primary auditory and visual areas. Mean responses for the spindle response areas are consistently very much larger than for the primary areas; response variability is relatively low. An analysis of variance and range test comparing means was completed on the data for each animal. The results of these analyses indicated that the mean response amphtudes in all four spindle fields were significantly larger than the means in primary areas at better than the 1 ~ level of significance. Thus, for a given preparation, mean spindle burst amplitudes were relatively stable and consistently very much larger in the nonspecific spindle regions. Spindle bursts from unresponsive regions of cortex were of extremely low amplitude or nonexistent and had correspondingly low variability (cf, Figs. 2 and 3). Temporal characteristics of spindle bursts. Correlations of occurrence and amplitude of association evoked responses are extremely high m all four cortical response foci in the chloralosed preparation [36]. If a related common system is responsible for spindling in all four cortical areas, the time of onset and temporal pattern of spindling activity ought to be essentially the same in all four nonspecific spindle response fields. General coincidence of occurrence of spindle bursts has been noted in many studies [21, 24]. In Fig. 4, paired tracings are taken from all possible combinations of spindle fields, and from these regions and primary sensory areas, in the cerveau isol6 preparation. Each pair of tracings was taken at a different time. The time of onset and general temporal pattern of mixed wave spindle bursts are essentially identical for all pairings of the four spindle response fields. The probability of such similar temporal distributions of spindle bursts by chance alone is extremely low. Comparisons of temporal distributions of spindling in the spindle fields and in primary auditory and visual cortical fields are shown in the right portion of Fig. 4. All primary sensory spindles are small or nonexistent (see below), but where they occur, the temporal distributions appear similar to those in the
272
PHILLIPS, DENNEY, ROBERTSON. HICKS AND [H()MPS()N
AmA
P~SA ~
.,az~,/I., ,L, ~2~..,, ag...11~ AMSA
' q r m ' - " V" "" ~11"~" " ~ ~
~-~-WT - "~V=',
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vl
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- I Sec AI
~.a ...~a.,.,J.~ h~.,.,IL g . . . L , . , ~ A -~h. ~ ' ~ " ' ~' =" "v ~.11, ~ . . . . . ~qlr v,,.rv ,
FIG. 4. Paired ECG records from all combinations of nonspeclfiC spindle response fields and from these regions and primary sensory areas. Cortical areas designated: PMSA, Posterior Middle Suprasylvlan Area; AMSA, Anterior Middle Suprasylvian Area; ALA, Anterior Lateral Area; PCA, Perlcruclate Area; AI, Primary Auditory; VI, Primary Visual.
TABLE MEANS AND STANDARD
ERRORS,
1
I N ~ W , OF S P I N D L E B U R S T A M P L I T U D E S AUDITORY
IN THE SPINDLE FOCI AND IN THE PRIMARY
ALA
for each sample) PCA AMSA
(n =
VISUAL AND
AREAS
10
PMSA
VI
AI
Pentobarbltal
:~ sT
490 38
440 37
460 26
370 36
90 9
150 19
Cerveau isol~
:~ sR
620 56
690 99
760 75
770 35
240 45
170 23
nonspecific spindle fields. The essentially identical temporal distributions in all four spindle response areas of spindle bursts was true only for mixed wave spindle bursts. In contrast, Type II wave spindle bursts are seldom present in more than one area at any given time, and appear to have no correspondence of temporal distribution with either Type II wave or mixed wave spindle bursts in other areas. Spindle bursts in sensory cortex. Mixed wave spindle bursts in primary sensory areas of the cortex are either small or not present (Figs. 2, 3, and 4 and Table 1). In somatic sensory cortex, sizable spindle bursts were found only along the anterior border of somatic area I in a band lying between the cruciate sulcus and the post-cruciate dimple, where the pericruciate associat:on response field and the primary motor cortex overlap (Figs. 2 and 3). Comparisons of simultaneous monopolar and bipolar records taken from the pericruciate spindle area and from
auditory area I are shown in Fig. 5. The upper tracing for each represents monopolar recording (actually against a distant skin indifferent electrode), and the lower tracing represents bipolar recording between this surface electrode and a small penetrating electrode inserted oerpendicular to the cortical surface to a depth of 2 mm directly below the surface electrode. Spindle bursts from the pericruciate area were considerably larger when recorded bipolarly than when recorded monopolarly. The surface monopolarly recorded bursts in these records were of the same amplitude as those recorded prior to insertion of the penetrating electrode. Such monopolar vs. bipolar comparisons are shown for a number of different cortical regions in Fig. 6. Records from association areas (a, b, c) all yield markedly larger spindles in the bipolar (lower) traces. In all other areas the bipolar spindle bursts are either of the same low amplitude as the monopolar surface records, or even smaller in amplitude.
NONSPECIFIC SYSTEMS AND CORTICAL PROJECTIONS
273
Bofo¢o AmlkeOk
bipolar
~
After Anesthetic
~ AI
AI
bipolar
_-
I .5 Mv
=
.
VI
- I Sec
FIG. 5. Simultaneous surface monopolar and surface-depth bipolar records from pericrucmte spindle area and primary auditory
a! ea.
ALA
AMSA
b \
~
d c
j
_.,~.~
e
g
[ SMv ) S~ec
FIG. 6. Simultaneous surface monopolar (upper traces) and surface-depth bipolar (lower traces) actiwty from several cortical areas.
The record from posterior SI [1] is particularly striking. Small but clear spindles are seen in the surface record; however, no spindles whatever are seen in the bipolar record. Monopolar surface and depth recordings taken from sensory cortices demonstrate that although primary evoked potentials show polarity reversal between surface and depth, spindles in these areas do not (see Fig. 7); the recorded spindles from surface and from depth are in phase. Further, when a local anesthetic is placed on the cortical surface, the evoked potentials are greatly attenuated while spindles are not. This contrasts with spindles recorded in association areas. Here, surface and depth records of spindles appear 180 ° out of phase, and when a small amount of local anesthetic is placed at the recording site, the spindles are essentially eliminated, leaving only very small, m-phase, spindles. Reversal of polarity between cortical surface and depth placements has been interpreted as evidence for the local generation of evoked potentials [23] and spindle bursts [30] and lack of this
PMSA
,~
I
100 MY
FIG. 7. Surface monopolar (lower traces) and depth monopolar (upper traces) records taken from association-spindle fields and from primary sensory regions. Left column shows evoked potentials and ECG tracings before, and fight column after, a drop of local anesthetic (procaine hydrochloride) was placed at the recording site. Sweep duration for evoked potentials--100 msec; for ECG-1 sec.
reversal may mean that the potentials recorded are the result of volume conduction from other areas [34]. These data, showing that the in-phase spindles in sensory cortex are not eliminated by topical local anesthetic, are consistent with this interpretation. Thus, when mixed wave spindle bursts do occur in sensory regions of the cortex, they may not be locally generated. The lack of spindle activity in primary sensory cortex seems not to be due to the suppression of spontaneous rhythms in the thalamic relay nuclei by afferent stimulation. Spindling was not observed in primary auditory or somesthetic cortices in the cerveau isol6 preparation, and records of spontaneous activity in visual cortex showed no evidence of spindling, whether the animal was in a normally lighted or almost completely darkened room. Nor can the absence of spindling be attributed to a physiological unresponsive cortex. Normally-appearing evoked potentials, showing polarity reversals with depth, were observed in all primary areas. Cortical distributionof reticular evokedresponses. Beginmng with the classical observations of Moruzzi and Magoun [25], several authors have noted that cortical responses to reticular stimulation tend to be more evident in certain regions of cortex, particularly sensory-motor and posterior areas [10, 13, 20]. In the present experiments the detailed cortical distribution of responses evoked by single shock stimulation of the midbrain reticular formation was compared with the cortical distribution of nonspecific association responses evoked by peripheral stimuli in the chloralosed preparation. The stimulating electrode was placed in the region of the tegmentum yielding maximum evoked reticular responses
274
PHILLIPS, DENNEY, ROBERTSON, HICKS AND I HOMPSON
A
1
-~ -~-l~ / -%/ -~., I / -%1~, { -x./-%/
~-, - ~ -d'l--d !
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!
MESENCEPHALICRETICULARFORMATION MESENCEPHALIC RETICULAR
FORMATION I .5 mV
!-t 100 mSEC
LIGHT FLASH
Q
IPSILATERAL FOREPAW 'r2mV
(
~
i-I IOOmSEC
C
MESENCEPHALICRETICULARFORMATION
]: 1mY
D
IPSIL~ERAL FOREPAW
I-4100mSEC
FIG. 8. Cortical dtstributlons of evoked responses to mesencephalic reticular single pulse electrical stimulation and association responses to peripheral stimuli. (A) Area PCA, (B) ALA, (C) AMSA and PMSA, and (D) photomicrograph showing placement of stimulating electrode.
to peripheral stimulation (cf, Method). The cortical distribution of short latency (4-7 msec) responses to reticular stimulation and association responses to peripheral stimuli are compared in Fig. 8. The distributions of responses are essentially identical. If the stimulating electrode in reticular formation is moved from the locus of maximum reticular responses, the relative amplitude distribution of cortical responses to reticular stimulation does not change, but absolute amplitudes of cortical responses decrease. Under conditions of our experiments we were never able to evoke any measurable responses in primary auditory, visual and somatic sensory areas of the cortex by single shock stimulation of the reticular formation. Buser and Borenstein [13] reported that repetitive electrical
stimulation of the midbrain reticular formation abolished cortical association responses to peripheral stimulation. We completed a recovery cycle analysis comparing responses evoked in cortex by single reticular shocks and peripheral stimuli. As shown in Fig. 9, the form of the interaction between reticular stimulus and peripheral stimuli does not appear to differ from the interaction between various peripheral stimuli. DISCUSSION
The results of these experiments indicate that the foci of maximum amplitude mixed wave spindle bursts on the cortex of the barbitalized or cerveau isol6 cat appear to correspond
NONSPECIFIC SYSTEMS AND CORTICAL PROJECTIONS % I00
¢ ~eo
q= -~. 60
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0-12
014
T~me Between
0i6
018
Shmuh (Sec)
FIG. 9. Recovery cycles of cortical association responses to peripheral stimuli and to mesencephalic reticular single pulse electrical stimulation. Relative response amplitude to the second of two stimuh as plotted as a function of time between stimuli.
exactly in location with the foci of maximum amplitude nonspecific association responses to peripheral sensory stimulation and foci of maximum amplitude short latency responses to electrical stimulation of the midbrain reticular formation in the chloralosed cat. There are thus four restricted areas of maximum mixed wave spindle bursts, two on the suprasylvian gyrus, one on the anterior lateral gyrus, and one on pericruciate cortex overlapping the dorsal portion of the primary motor cortex. There are no appreciable differences in cortical distribution of spindle bursts between the pentobarbital and cerveau isol6 preparations, although spindle activity is often somewhat more pronounced in the latter preparation. The onset times and temporal distributions of mixed wave spindle bursts are identical in all four cortical foci of maximum response. These results are all consistent with the hypothesis that spindle bursts and evoked association responses share a common cortical projection system. Spencer and Brookhart [29, 30] analyzed the intracortical distribution of spontaneous spindle waves in terms of the intcacortical patterns of augmenting and recruiting responses. They concluded that all spindle waves could be classified as being like augmenting waves (Type I), or like recruiting waves (Type II), or a combination of these (mixed type). Our classification of spindle bursts was based on their analysis. Two basic surface configurations of spindle bursts were seen in our experiments, a predominantly positive type (mixed wave) and a predominantly negative type (Type II wave). About 95 ~ of the spindle burst activity in our experiments was of the mixed wave type. Pure Type II wave spindles were seen only about 5 ~o of the time and only on the anterior border of the anterior lateral response focus and the posterior and ventral borders of the pericruciate response focus (i.e., primarily in somatic sensory area I). Onset t~mes and temporal distributions of Type II wave spindle bursts in these areas do not correspond to mixed wave bursts in any of the spindle response areas or to each other in the two anterior response areas. These findings provide further evidence for the necessity of a categorization scheme such as that developed by Spencer and Brookhart. Mixed wave spindle burst activity in primary sensory areas of the cortex was limited to regions bordering the nonspecific spindle response foci in our experiments. In somatic sensory area I spindle bursts were sizeable only along the anterior border where the pericruclate spindle response field overlaps. This pericruciate field is not coextensive with the primary
275 motor cortex either, overlapping only the dorsal portion dorsomedial to the coronal sulcus, and extending anterior to motor cortex. Thus the pericruciate spindle focus by no means corresponds to sensory-motor cortex, a portion of motor cortex and the bulk of somatic sensory area I exhibiting either very low amplitude spindle bursts or no measurable spindles. Spindle burst activity in auditory and visual areas was limited to regions bordering the suprasylvian gyrus. In primary sensory areas of the cortex, bipolar recording across the cortex yielded lower amplitude spindle bursts than did monopolar surface recording, and closer analysis indicated the records taken from surface and from depth were in phase. Bipolar recordings taken in the pericruciate and posterior association spindle response fields, in contrast, gave substantially larger spindle bursts than did surface monopolar recordings, and the surface and depth records were out of phase. Further, local anesthetic applied to the cortex eliminates spindles in the association areas, but not in primary sensory areas. These data suggest that mixed wave spindle burst activity recorded by surface electrodes on sensory cortex is not generated intracortically at the recording sites, at least under the conditions of our experiments, in contrast to spindle activity in association response foci. Although the relations between spindle bursts and recruiting responses are still not completely understood, these data may reopen the issue concerning the existence of recruiting in primary sensory cortex [19, 31]. It must be emphasized that our analysis is limited to the mixed wave spindle bursts, by far the most frequently occurring type, in which Spencer and Brookhart [30] Type I and mixed waves predominate. These resemble what Andersen and Andersson [5] term compound spindles, which they report as occurring simultaneously over widespread cortical areas. They also describe local spindles, occurring without concomitant spindle activity in other areas, that are similar to the infrequently occurring Type II wave spindles described here. These local spindles, generated in specific sensory thalamic nuclei and corresponding cortical areas [5, 6] appear to be mediated by different thalamo-cortical systems than the predominant mixed wave spindles we have studied here. Our findings on the cortical distribution and occurrence of mixed spindles may be interpreted in terms of a unitary pacemaker with at least principal projections to the four association areas. This is consistent with other studies showing abolition of cortical spindling and recruiting by lesions in the rostral pole of the thalamus [15, 18, 28, 38], and by lesions in the inferior thalamic peduncle [28]. The identity of cortical distributions of short latency responses to single shock stimulation of the midbrain reticular formation and longer latency association responses to peripheral stimulation, the similar recovery cycle function obtained for reticular and peripheral stimuli, and the identical cortical distribution of mixed spindle bursts would all seem to suggest a common system. However, Blgnall's [7] report that large lesions in the medial thalamus and rostral midbrain reticular formation do not eliminate cortical association responses raises some question as to what the system may be. Although the preponderance of evidence implicates the reticular formation and medial thalamic nuclei in the cortical association response [1, 2, 3, 11, 14, 32, 34], the possibility of multiple parallel inputs to the association areas has also been suggested [12]. The well localized distribution of mixed wave spindle activity described here may have implications for the function
276
PHILLIPS, DENNEY, ROBERTSON, HICKS AND THOMPSON
of these cortical regions in the behavmg ammal. The transition from cortical spindle activity to a desynchronized E E G has c o m m o n l y been used as an indicant of an aroused or attentive a m m a l [5, 24]. Since spindle activity occurs predominantly in the four association response foci, it follows that these are the cortical regions which would most clearly or reliably display desynchronization. Thus, the greatest differences in cortical activity between a drowsy animal and an attentive
or aroused one may occur In the association response legions These areas may thus be intimately involved in general arousal or attentive processes. The observations that evoked responses to reticular formation stimulation also occur only in these cortical regions, and other studies demonstrating an increase in unit activity in association response areas during periods of behavioral orienting [33], offer further support for this view.
REFERENCES
1. Albe-Fessard, D., D. Bowsher and A. Mallart. R6ponses 6voqu~es dans la formation r6ticul6e bulbaire au niveau du noyau giganto cellularis d'OlzewskL R61e de ce noyau dans la transmission vers le centre m6dlan du thalamus des afferences somatiques. J. Physiol. (Paris) 54: 271, 1962. 2. Albe-Fessard, D. and A. Fessard. Thalamic integrations and their consequences at the telencephahc level. In: Progress in Brain Research, edited by G. Moruzz~, et al. Vol. I, Brain Mechanisms. Amsterdam: Elsevier, 1963, 115-148. 3. Albe-Fessard, D. and A. Rougeul. Activit6s d'origine, somesth~slque 6voqu6es sur le cortex non-sp~cifique du chat anesth6sl6 au chloralose: r61e du centre m6dian du thalamus. Electroenceph. clin. Neurophysiol. 10: 131-151, 1958. 4. Amassian, V. E. Studies on organization of a somesthet~c association area, including a single umt analysis. J. Neurophysiol. 17: 39-58, 1954. 5. Andersen, P. and S. A. Andersson. Physiological Basis of the Alpha Rhythm. New York: Appleton, Century, Crofts, 1968. 6. Andersen, P., S. A. Andersson and T. Lomo. Nature of thalamocortical relations during spontaneous barbiturate spindle actiwty. J. Physiol. 192: 283-307, 1967. 7. Btgnall, K. E. Effects of subcortical ablations on polysensory cortical responses and interactions in the cat. Expl Neurol. 18: 56-67, 1967. 8. Bremer, F. Cerveau 'hsol6" et physiologie du sommeil. C.R. Soc. Biol. Paris 118: 1235-1241, 1935. 9. Brookhart, J. M. and A. Zanchetti. The relation between electrocortical waves and responsiveness of the corticospmal system. Electroenceph. clin. Neurophysiol. 8:427 ~a,4, 1956. 10. Bruner, J. Affer6nces vlsuelles non-primalres vers le cortex ~r6bral chez le chat. J. Physiol. (Paris) 57: Suppl. 12, 1-120, 1965. 11. Buser, P. Subcorhcal controls of pyramidal acUvlty. In" The Thalamus, edited by D. P. Purpura and M. D. Yahr. New York: Columbia University Press, 323-344, 1966. 12. Buser, P. and K. E. Bignall. Nonprimary projections on the cat neocortex. Int. rev. Neurobtol. 10: 111-t65, 1967. 13. Buser, P. and P. Borenstein. Suppression 61ective des r6ponses "associatives" par stimulation r6ticulaire chez le chat sous anesth6sie profonde au chloralose. J. Physiol. (Paris) 49: 86-89, 1957. 14. Buser, P., P. Borenstein and J. Bruner. Etude des syst~mes "assoclatifs" visuels et auditifs chez le chat anesth6si6 au chloralose. Electroenceph. clin. Neurophysiol. 11: 305-324, 1959. 15. Chow, K. L., W. C. Dement and S. A. Mitchel. Effects of lesions of the rostral thalamus on brain waves and behavior in cats. Electroenceph. clin. Neurophysiol. 11: 107-120, 1959. 16. Dempsey, E. W. and R. S. Morison. The interaction of certain spontaneous and induced cortical potentials. Am. J. Physiol. 135: 301-308, 1942. 17. Derbyshire, A. J., B. Rempel, A. Forbes and E. E. Lambert. The effects of anesthetics on action potentials in the cerebral cortex of the cat. Am. J. Physiol. 116: 577-596, 1936. 18. Hanberry, J., C. Ajmone-Marsan and M. Dilworth. Pathways of nonspecific thalamo-cortical projection system. Electroenceph, clin. Neurophysiol. 6: 103-118, 1954.
19. Hanberry, J. and H. Jasper. Independence of diffuse thalamocortical projection system shown by specific nuclear destruction. J. Neurophysiol. 16: 252-271, 1953. 20. Ilyutchenok, R. Y. and V. S. Zmevich. Short latency reticulocortical potentials: Effect of muscarinic anticholinerglc drugs. Neuropharmacology 9: 433 a.~9, 1970. 21. Jasper, H. H. Unspecific thalamocortical relations in: Handbook ofPhyswlogy, Neurophysiology, edited by J. Field, H. W. Magoun and V. E. Hall. Vol. 2. Washington, D.C.American Physiological Society, 1307-1322, 1960. 22. Jasper, H. H. and C. Ajmone-Marsan. A Stereotaxw Atla~ oJ the Diencephalon of the Cat. Ottawa" National Research Council of Canada, 1954. 23. L1, C. L., C. Cullen and H. Jasper. Laminar mlcroelectrode studies of specific somato-sensory cortical potentials. J. Neurophysiol. 19: 111-136, 1956. 24. Lindsley, D. B. Attention, consciousness, sleep and wakefulness. In: Handbook of Physiology, Neurophysiology, Vol. 3, edited by J. Field, H. W. Magoun and V. E. Hall. Washington D.C.: American Physiological Society, 1553-1593, 1960. 25. Moruzzi, G. and H. W. Magoun. Brainstem reticular formation and activation of the EEG. Electroenceph. clin. Neurophysiof. 1: 455473, 1949. 26. Nauta, W. J. H. and H. G. J. M. Kuypers. Some ascending pathways in the bramstem reticular formation. In: Reticular formation of the brain, edited by H. H. Jasper, et al. Boston: Little, Brown, 1958, pp. 3-30. 27. Ralston, B. and C. Ajmone-Marsan. Thalamlc control of certain normal and abnormal cortical rhythms. Electroenceph clin. Neurophysiol. 8: 559-582, 1956. 28. Skinner, J. E. and D. B. Lindsley. ElectrophyslologJcal and behavioral effects of blockade of the nonspeclfic thalamocortical system. Brain Res. 6:95-118, 1967. 29. Spencer, W. A. and J. M. Brookhart. Electrical patterns of augmenting and recrmting waves in depths of sensorimotor cortex of cat. J, Neurophysiol. 24: 26-49, 1961. 30. Spencer, W. A. and J. M. Brookhart. A study of spontaneous spindle waves in sensonmotor cortex of cat. J. Neurophysiol. 24: 50-65, 1961. 31. Starzl, T. E. and H. W. Magoun. Organization of the diffuse thalamlc projection system. J.Neurophysiol. 14: 133-146, 1951. 32. Thompson, R. F. Thalamocortical orgamzatlon of association responses to auditory, tactile, and visual stimuli in cat. Proc. X X l l lnt. Congr. Physiol. Sci. Leiden. 48: 1057, 1962. 33. Thompson, R. F., L. A. Bettinger, H. Birch, P. M. Groves and K. S. Mayers. The role of synaptm inhibitory mechamsms In neuropsychological systems. Neuropsychologia 7: 217-234, 1969. 34. Thompson, R. F., R. H. Johnson and J. Hoopes. Organization of auditory, somatic sensory and visual projections toassociation fields of cerebral cortex in the cat. J.Neurophysiol. 26: 343-363, 1963. 35. Thompson, R. F. and R. M. Sindberg. Auditory response fields in association and motor cortex of cat. J. Neurophyswl. 23: 87-105, 1960. 36. Thompson, R. F., H. E. Smith and D. Bhss. Auditory, somatic sensory and visual response interactions and mterrelauons Jn association and primary cortical fields of the cat. J Neurophysiol. 26: 365-378, 1963.
NONSPECIFIC SYSTEMS AND CORTICAL PROJECTIONS
277
37. Velasco, M. and D. B. Lindsley. Role of orbital cortex in regulation of thalamocortical activity. Science 149: 1375-1377, 1965.
38. Weinberger, N. M., M. Velasco and D. B. Lindsley. Effects of lesions upon thalamically induced electrocortical desynchronization and recruiting. Electroenceph. clin. Neurophysiol. 18: 369-377, 1965.