Anticipatory recall deficit after cingulumotomy in rats

Anticipatory recall deficit after cingulumotomy in rats

EXPERIRIESTAL 32, 141-151 NEUROLOGY Anticipatory Recall (1971) Deficit TURNER After MCLARDY Cingulumotomy 3 Myerson Research Laboratory, Bos...

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EXPERIRIESTAL

32, 141-151

NEUROLOGY

Anticipatory

Recall

(1971)

Deficit TURNER

After MCLARDY

Cingulumotomy 3

Myerson

Research Laboratory, Boston State Boston, Massachusetts 02124

Received

March

30.1971;

revision

in Rats

vcceivcd

Hospital,

Nay

3,197l

The terms “cingulum” and “fasciculus cinguli” as defined in the present report help resolve some apparent contradictions in the anatomical and behavioral literature on lesions affecting white matter of the rat’s cingulate gyri. Eleven rats with no full bilateral brain-structure damage in common except transection of the cingulum, displayed sustained loss of “anticipatory recall” but no loss of “perceptual recognition” in the immediate rerunning of novel pathways on a multichoice raised maze. Three of six littermates with unilateral transection of the cingulum accompanied by bilateral transection of the fasciculus cinguli. displayed fluctuating deficit in anticipatory recall. These findings are interpreted within a concept of evolution of cingulate cortex for the memorizing and subsequent inferenced recalling of rewarded long time-span sequences of acts beyond the operating time spans of hippocampal CA3 and C,41. Introduction

The cingulum is conventionally categorized as a long association bundle, that is to say, a relatively discrete fascicle of long axons connecting cortex to cortex within the same hemisphere. It has, of recent years, however, been held by some experimental anatomists to include nonassociation elements within the white matter related to the cingulate cortex. Thus, Krieg (1Oj and Domesick (5) included within it in rats the projection system from anterior thalamic nuclei to cingulate cortex (the latter using the term “fasciculus cinguli” as synonymous with “cingulum”), whilst Nauta and Whitlock (15) included within it, also in rats, projection fibers originating in midline and intralaminar thalamic nuclei. Again, Yakovlev and Locke (23) described corticostriatal branches of the monkey’s cingulum. Domesick (5) described a “fasciculus cinguli” projecting to cingulate and area presubicularis cortex, and confined to a fairly solid bundle within the medial sector of the external medullary lamina of the cingulate white matter at supracallosal levels. She denied appreciable associational contributions from anterior cingulate or more rostra1 mesial cortex, but was ap1 Supported the National

in part by Public Health Service Grant 2-R01 Institute of Neurological Diseases and Stroke. 141

NS

09755-02

COM

from

14.2

MC

LARDY

parently not closely scrutinizing the lateral sector of the external medullary lamina, and seemingly made no search for axonal degeneration within area parasubicularis or area entorhinalis. She had previously (4) described the lateral sector as containing association fibers from the dorsomedial corner of the anterior cingulate cortex (as well as thalamic projections to cortex of the convexity), and the internal meduallary lamina as being occupied largely by fiber systems projecting from cingulate cortex to subcortical regions. White (21) was evidently depicting the whole of the external medullary lamina short of the superior longitudinal bundle in his Fig. 6. If his highly tenuous arguments for allocating the anterior thalamic projection fibers to lateralmost “part a” be discounted and reassessed in favor of allocation to “part d” (as would seem permissible from his data), his parcellation becomes topologically consistent with Domesick’s findings, given that he was reporting upon terminal axonal degeneration within area entorhinalis as well as Rose’s (16) full “regio presubicularis” (i.e., area parasubicularis as well as area presubicularis) . One may reasonably conclude (and it seems circumstantially supported by my observations reported below) that the longitudinally coursing elements within cingulate supracallosal white matter in rats comprise two relatively discrete systems : rostrally augmenting predominantly medially situated projection fibers from thalamus to cingulate and presubicular cortex; and caudally augmenting predominantly laterally situated association fibers connecting mesial frontal and cingulate cortex with cortex of the hippocampal gyrus. as well as with each other. An immediate corollary to such topological clarification, if correct, is that it is inadmissible to determine the degree of transection of cingulate longitudinal white matter by quantifying retrograde cell degeneration within anterior thalamic nuclei. This consideration could be responsible for the apparent contradiction between the conclusions of Thomas and Otis (18) and of Thomas and Slotnick (19) using identical maze tests and species. The former concluded that bilateral cingulumotomy was the common factor lesion most likely responsible for the deficit in maze learning in their nine rats, all of which (as manifest from their text and illustrations) had bilateral transection of the lateral as well as the medial sector of the cingulate white matter at midcallosal levels. The latter concluded that bilateral cingulumotomy in 24 rats was not followed by significant learning deficit on the maze. Their 15 electrolytic lesions, however, essentially spared the lateral sector of cingulate white matter; and it is never claimed that all nine of their knife-cut lesions bilaterally affected the lateral sector of the external meduallary lamina. In other words, although anterior thalamic nuclei were in several cases found heavily degenerated, the cingulum was

CINGULUM

probably

not bilaterally

damaged in a significant

143 number of their 24 ani-

mals. In the present report, therefore, when referring to supracallosal white matter, “f asciculus cinguli” will be restricted to the thalamic projection systems within the medial sector of the external medullary lamina: “cingulum” to the association system within the lateral sector. In defining the lesions under Results, no distinction will be made between external and internal medullary laminae; only between the medial and the lateral sectors of the white matter, as defined under Methods. The term “entorhinal cortex” will be used as synonymous with “hippocampal gyrus,” comprising entorhinal area, plus parasubicular area, plus presubicular area. Methods Twenty-nine albino rat pups 13-16 days old were anesthetized by ether during hypothermia, and bilateral selective transection of the cingulum, at varying supracallosal anteroposterior (AP) levels, was attempted. In 14 instances this was done by electrocautery ; in nine, by single transverse incisions with an ophthalmic lancet; and in six, by looping a curved surgical needle through scalp and skull from left to right of the midline down to callosal level and then sawing upwards with nylon thread. Seven male and seven female unoperated littermates were employed to establish a base-line normal range for the maze memory tests. After weaning, all the animals were familiarized with the “start,” “diagonal.” “ zig-zag” (minus section +‘A”), and roofed-walled “goal” portions of a complex raised unwalled maze (Fig. 1). During adolescence and young adulthood memory tests were performed on this multiroute vibratable maze (13) with the circle-loop portion now open and four different arrangements of block points leaving one new open pathway from start to goal. Each novel route, tested during a different week, was run five times with 30 set at goal between each run; temperature, lighting, time of day, and appetitive state being kept constant. In manifesting anticipatory recall, rats seemed to be using a concept of the maze and inferring the pattern of the pathway ahead. The arrangement found most strikingly discriminative between anticipatory recall and perceptual recognition was the one illustrated, open, in Fig. 1 where, at the five-ways intersection, the animal had to turn more than 90 deg away from the direction of its final goal. Anticipatory recall was judged to be present when, at the second, third, fourth, or fifth run, a rat leaped across the fiveways intersection from point A to point B without pause, It was still considered to be present on the criterion of the performance of the unoperated controls if, after nonhesitant progress to the five-ways intersection, it only nosed into blocked routes 1 or 2 (or both) before progressing into route

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4. There was a tendency for control animals, as much as intact-recall operates, especially on the second run, to sit for a period at the five-ways intersection with nose pointing half-way between routes 1 and 2. Deficit in anticipatory recall, with dependence upon perceptual recognition, was recorded when an animal paused, at the least, at most choice points between start and goal on each run but duly reached the goal without coaxing. Deficit in perceptual recognition, obscuring any deficit in recall, was recorded if the animal persistently required directional coaxing on all five runs. Fluctuating deficit in anticipatory recall was recorded in three animals in which recall was present in running two of the novel pathways but absent in the other two. Varying degrees of spontaneous activity among the animals, such as between the more sprightly females and more ponderous males, were compensated for, so far as possible, by varying the intensity of the maze vibration. As reported elsewhere (13), hunger, which anyhow tends to motivate males more strongly than females during daytime, was unnecessary, the rats being adequately reward-motivated by the walled and roofed goal. The noisy vibrating tambourine elicited some curosity, but never aversion, and appeared to operate through generalized “arousal.” In 14 operated rats and five controls the cerebral hemispheres were sep-

FIG. 1. Scale drawing of the multiroutable raised (80 cm above floor) unwalled maze, showing route 4 open. A to B, shortest leapable way on route 4 at five-ways intersection ; G, walled and roofed goal ; S, start point; V, vibrated leg of maze; 1, 2, 3, 4, different routes open on successive weeks of testing. Calibration mark : 30 cm.

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arated at autopsy by midline sagittal section and then serially sectioned sagitally starting from the mesial surface. In the remainder, bilateral serial sectioning was performed in the coronal plane. Every fifth, formalin-fixed paraffin-embedded, section was saved and prepared by the Luxol-fast blue and cresyl violet method for combined display of myelin and cell bodies. In both planes of sectioning the transition within the cingulate white matter from the medial sector’s fasciculus cinguli to the lateral sector’s cingulum was assumed to occur, at all callosal levels, at a point 275 p lateral to the most mesial longitudinal fibers. In recording the AP levels of lesions, the junction point between anterior and posterior cingulate cortex was taken to be at the level of the rostralmost tip of the alveus of the dorsal limb of the hippocampus. Results

Eight of the 29 operated rats (17 male, 12 female) displayed persistent deficit in perceptual recognition and will be the topic of a separate report, Eleven displayed sustained deficit in anticipatory recall, three showed fluctuating deficit in anticipatory recall, and the remaining seven exhibited no memory deficit whatsoever. In each of the 11 displaying sustained deficit in anticipatory recall but no deficit in perceptual recognition (Table 1 ), histology revealed bilateral

SUMMARIZED

LESIONS

TABLE

1

11

DISPLAYING

IN

THE

IN

ANTICIPATORY

RATS

RECALL

SUSTAINED

Left

No. 1

2 3 4 5 6 7 8 9 10 11

Cingulum transected A A A A A A A AP AP P P

Fascic. cinguli transected

Right

Fornix (% TS)

A A A A A A AP AP P P

Q A, anterior cingulate percentage transected.

DEFICIT

0

corpus callosum (% length)

90 100 50 50 100 20 30 100 80 level;

F, female;

70 AP 50 A 40 A 30A 30A 30AP SOAP 40 AP 3OP M,

Fornix (% TS) 90 50 100 20 -

male;

P, posterior

Fascic. cinguli transected

Cingulum transected

A A A A AP AP AP P P P cingulate

A A A A A AP AP AP P P P level;

Sex M M M F M M F F M M F ?Jc TS,

146

MC

LARDY

CINGULUM

147

full transection of the cingulum ; and there was no other anatomical entity bilaterally fully transected except the fasciculus cinguli in nine. The remaining two had unilateral transection of the fasciculus cinguli (Fig. 2). There was no instance of bilateral cingulum transection with bilateral sparing of the fasciculus cinguli. Five of the cingulum transections were confined, bilaterally, within anterior cingulate levels, the most anterior (No. 3) being within rostra1 septal levels. The smallest lesions associated with sustained deficit in anticipatory recall were in a lancet-operated animal in which coronal sectioning revealed only 200-p AP puncture slits cutting into, and not beyond, the cingulate white matter at mid-anterior cingulate levels on both sides, the corpus callosum and one fasciculus cinguil being essentially spared. In the three rats displaying fluctuating deficit in anticipatory recall (Table 2, Nos. 12, 13, l-l), histology revealed unilateral transection of the cingulum with bilateral transection of the fasciculus cinguli (Fig. 3) ; but there were also three animals (Nos. 15, 16, 17) with the same triad of transections but no deficit in recall on any test (Fig. 4 ) . At the times of testing and in subsequent reviews of the protocols, no variable could be discovered (such as sex, distraction, or intensity of arousal) that tended to correlate with the presence or absence of recall in the fluctuating cases. All three, however, proved to have anterior level transections, that of rat No. 14 being the most rostra1 in the whole series; two of the three deiicitless ones, to have posterior level transections. The four remaining animals, devoid of any deficit, proved to have purely unilateral, ipsilateral transections of both the cingulum and the fasciculus cinguli. There was no instance of bilateral transection of the fasciculus cinguli with bilateral integrity of the cingulum. Discussion

Damage to cingulate tortes was nil to negligible. Damage to the corpus callosum was almost always appreciably more extensive, AP, than to the FIG. 2. Coronal section of brain of rat No. 6 illustrating bilateral transection of cingulum and unilateral (right) transection of fasciculus cinguli, at posterior septal level ; corpus callosum gone. L. left hemisphere. FIG. 3. Coronal section of brain of rat No. 13 illustrating unilateral (left) transection of the cingulum with bilateral transection of the fasciculus cinguli, at fornix level just rostra1 to hippocampus. L, left hemisphere.

FIG. 4. Sagittal fasciculus cinguli cingulum.

section of right hemisphere of rat No. 15, illustrating transection by a lesion (at arrow) which does not extend to the laterality

of of

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TABLE LESIONS

IN

THE

10

RATS

WITH

LESSER

2 No

OR

Left

No. 12 13 14 15 16 17 18 19 20 21

A A A AP P AP A A P

a Abbreviations

cinguli transected A A A A AP P AP A A P as in Table

IN

RECALL

a

Right

Fascic.

Cingulum transected

DEFICXT

Fascic. cinguli

Corpus Fornix

(% TS) 20 10 100

60 30

callosum

(%

length) 50 AP 30A 20A 10A 20A 60AP 30A 10A 1OP

Fornix

(%

TS) 10 -

tran-

sected A A A A P P -

Cingulum transected A -

-

Sex M M M M M F M F M F

1.

cingulate white matter, apparently due to vascular factors. Nevertheless, the data summarized in Tables 1 and 2 seem logically almost to exclude callosum damage from being causally related to the deficit in anticipatory recall. Hence, any crossing branches of the cingulum in rats, such as described by Yakovlev and Locke (23) in monkeys, can almost be discounted as necessarily contributing to the deficit. The fornices seem completely exonerated from responsibility. The tabulated data would clearly point to the only 11 instances of sustained deficit in anticipatory recall having with high probability been caused by the only 11 instances of bilateral cingulum transection, although it cannot be excluded that superadded unilateral transection of the fasciculus cinguli may be also necessary for the deficit. An important feature is that anterior cingulate level lesions, as rostra1 as anterior septum, were as productive of the deficit as were posterior cingulate ones, since this indicates that the essential portion of the cingulum system for anticipatory recall lies still more rostrally, in rostralmost cingulate cortex, frontal cortex, or both. This fits with Barker’s (2) finding of a deficit in complex sequential lever tests in rats after bilateral anterior cingulate cortex lesions but not after posterior cingulate ones, and also with Slotnick’s (17) observation of a deficit in a sequential organization of maternal activities in rats after bilateral cingulate cortex ablations. The data in Table 2 indicate that in some cases of unilateral integrity of the cingulum but bilateral transection of the fasciculus cinguli, some ad-

CINGVLVM

149

ditional unidentified physiological variable can cause a deficit in anticipatory recall. Anatomically, the data suggest that a prerequisite for such fluctuating deficit is that the fasciculi cingulorum must be cut at anterior levels, i.e., before they have projected appreciably into cingulate cortex. The over-all findings, therefore, seem to point to anticipatory recall being dependent upon the functioning of a primary, f rontal-cingulate-entorhinal, cingulum association system receiving secondary support from a thalamic projection system. Presumably the main confluence of the two systems lies within the cingulate cortex, rather than in entorhinal cortex, since this would furnish a rationale for the evolution of primordial (cingulate) neocortex, as a means whereby records of rewarded sequences of acts, spaced in time beyond the time spans of hippocampal CA3 and CA1 (9), could be “memorized” for future guidance. The evolutionary survival value would be that the possessors of such cingulate cortex could, for instance, escape from a predator within reasonably familiar territory by high-speed inf erencing (i.e. anticipatory recall) without having to perceptually check-recognize each choice-point en route, as do rats after bilateral cingulumotomy. With the evolutionary expansion of neocortex, the recording mechanism presumably became at least potentially independent of the cingulate, or any other particular locus of, network-computer neocortex ( 11) in the adult. During the “behavior formative period” (12) the cingulate. like all other neocortex, receives its initial values programming from hippocampal CA3 and CA1 through fornix-fasciculus cinguli signalling (9). Thereafter the ethologically mature adult becomes essentially independent of such circuitry. In ethologically immature animals, such as are most laboratory animals and certainly the albino rat, there apparently remains at least some dependency upon input through the fasciculi cingulorum. According to the foregoing analysis no sustained deficit in anticipatory recall should occur after bilateral cingulumotomy in ethologically matured animals such as, most notably, normally reared human beings. Postoperative patients have, in fact, been reported to display only a transient “deficit in ability to locate past events correctly in temporal sequence” (22), some weeks or months of “easement in disabling preoccupation with pain or severe emotional balance” ( 1, 3, 7)) and a brief period of “impairment in recall of verbal memoranda” after stimulation of the dominant hemisphere’s cingulum (6). One would predict some anatomical tie-in of the primary cingulum anticipatory recall mechanism with the frontal lobe contingent-negative-variation electroencephalographic phenomenon seen in man during “expectancy” situations (20), and of the secondary fasciculus cinguli booster system with the hippocampal theta wave related to anticipated reward in experimental animals. Howsoever that may be,

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there clearly remains something nodally indispensable about that portion of the older cortex into which the cingulum circuitry ultimately plays, directly or via the presubiculum (8)) namely, the lateral entorhinal cortex (area entorhinalis), which, even in adults, cannot be bilaterally damaged with impunity ( 14). References 1. BALLANTINE,

H.

T.,

W.

L. CASSIDY, N. B. FLANAGAN, and R. MARIXO. 1967. cingulotomy for neuropsychiatric illness and intractable pain. J. Ncurosurg. 26 : 488-495. BARKER, D. J. 1967. Alterations in sequential behavior of rats following ablation of midline limbic cortex. J. Camp. Physiol. Psychol. 64 : 453460. BROWN, M. H., and J. A. LIGHTHILL. 1968. Selective anterior cingulotomy : a psychosurgical evaluation. J. Ncwoszwg. 29 : 513-519. DOMESICK, V. B. 1969. Projections from the cingulate cortex in the rat. Brai~ Rcs. 12 : 296320. DOMESICK, V. B. 1970. The fasciculus cinguli in the rat. Brain Res. 20 : 19-32. FEDIO, P., and A. K. OMMAYA. 1970. Bilateral cingulum lesions and stimulation in man with lateralized impairment in short-term memory. Ezp. Neural. 29 : 8491. FOLTZ, E. L., and L. E. WHITE. 1962. Pain “relief” by frontal cingulumotomy. J. NeuYosurg. 19 : 89-100. KARTEN, H. J. 1963. Projections of the parahippocampal gyrus of the cat. AX&. Rec. 145 : 247-248. KILMER, W. L., and T. MCLARDY. 1971. A diffusely programmed but sharply trainable hippocampus model. Inter&z Sci. Rep. No. 14, Air Force Office of Scientific Research. Arlington, Virginia. KRIEG, W. J. 1947. Connections of the cerebral cortex. I. The albino rat. J. Comp. Neural. 86 : 267-394. MCCULLOCH, W. S. 1964. Reliable sysetms using unreliable units. Res. Publ. Ass. Rrs. New. Menf. Dis. 42 : 19-28. MCLARDY, T. 1968. Fornix function during behavior-formative age. Sci. Proc. Awer. Psychiaf. Ass. 124 : 42-43. MCLARDY, T. 1970. Memory consolidation in rats with sulfide-loaded hippocampal zinc-rich synapses. Exp. Neural. 29 : 468-472. MCLARDY, T. 1970. Memory function in hippocampal gyri but not in hippocampi. Znt. J. Neuvosci. 1: 113-118. NAUTA, W. J. H., and D. G. WHITLOCI<. 1954. An anatomical analysis of the non-specific thalamic projection system, pp 81-104 IX “Brain Mechanisms and Consciousness.” Blackwell. Oxford. ROSE, M. 1929. Cytoarchitektonischer Atlas der Grosshirnrindes der Maus. J. Psychol. Newel. (Lpz.) 40 : l-51. SLOTNICK, B. M. 1967. Disturbances of maternal behavior in the rat following lesions of the cingulate cortex. Behavior 29 : 204-235. THOMAS, G. J., and L. S. OTIS. 1958. Effects of rhinencephalic lesions on maze learning in rats. 1. Cov#. Physiol. Psychal. 51 : 161-166. THOMAS, G. J., and B. M. SLOTNICK, 1962. Effects of lesions in the cingulum on maze learning and avoidance conditioning in the rat. J. Contp. Physiol. Psychol. 55 : 1085-1091.

Stereotaxic anterior

2. 3. 4. 5. 6. 7. 8. 9.

19. 11. 12. 13. 14. 1.5.

16. 17. 18. 19.

CINGULUM

20. 21. 22. 23.

151

W. G. 1968. Electric signs of expectancy and decision in the human brain, pp. 361-396. In “Cybernetic Problems in Bionics.” Gordon 8: Breach. New York. WHITE, L. E. 1959. Ipsilateral afferents to the hippocampal formation in the albino rat. I. Cingulutn projections. J. Co~rzp. Nrurol. 113 : l-41. WHITTY, C. W. M. 1966. Some early and transient changes in psychological function following anterior cingulectomy in man. 11zt. J. Ncrfvol. 5 : 403-409. YAKOVLEV. P. I., and S. LOCKE. 1961. Limbic nuclei of thalamus and connections of limbic cortex. III. .-11-rll. Xrtrrol. 5 : 364-400.

\YAI.TER,