Effect of electrical stimulation of the brain on visually controlled (attentive) behavior in Macaca mulatta

EXPERIMENTAL

NEUROLOGY

49,

203-220 (1975)

Effect of Electrical Stimulation of the Brain Controlled (Attentive) Behavior in Macaca EVA BAKAY

PRAGAY, ALLAN HELEN

Division

OSHIMA,

F. AND

MIRSKY, STEVEN

ARNOLD

of Psychiatry, Boston University School Boston, Massachusetts 02118

Received

April

18,1975;

C. FULLERTON,

BARBARA W.

revisiorb receivrd

May

on Visually mu/atto

1

of Medicilze,

15,197s

Electrical stimulation of various subcortical regions of the brains of five Macaca mulatta monkeys was conducted during the performance of a learned visual attention task. This required the animal to press for a red (positive) stimulus and to withhold responses to green or blue (negative) stimuli. Errors in performance were more frequently induced by the stimulation of the lower brain stem (midbrain and pons) than that of the thalamus. Omission errors (not responding to the positive stimuli) were most frequently elicited by stimulation of the mesopontine reticular formation or structures which are anatomically and functionally related to it. In contrast, commission errors (responding to negative stimuli) resulted most frequently from the stimulation of specific sensory systems or from areas closely related to them.

INTRODUCTION Impaired attentiveness is a symptom of a number of human diseases (schizophrenia, petit ma1 epilepsy) for which it has been speculated that somepathological involvement exists in the region of the brain stem reticular formation (9, 10, 13, 14). Since direct examination or manipulation of this region of the brain is not feasible in human subjects, one approach to the study of this problem has been to make use of animal models. This involves training monkeys to perform tasks designed to be analogous to those used to study attention impairment in man (10, 13, 20). Manipula1 Supported by NIMH (now ADMHA) grants from the U.S. Public Health Service : MH-12568 and 5-K5-MH-14,915 (Research Scientist Award to Allan F. Mirsky). Some of these results were presented at the December, 1973 meeting of the Eastern EEG Society, and were published in the abstracts of that meeting. The authors acknowledge the advice and assistance of Dr. Daniel Snyder of Yale University in implementing the electrode technique used in this study. 203 Copyright All rights

0 1975 by Academic Press, Inc. of reproduction in any form reserved.

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ET

AL.

tion of the brains of the monkeys can then be performed in various ways in order to test hypotheses concerning the pathophysiology of disturbed attention. In one prior study of monkeys with implanted intracerebral electrodes, it was found that impairment in the performance of a visual attention task could be achieved by electrical stimulation of certain regions of the midbrain and lower brain stem. Effective stimulation points were virtually absent elsewhere (13). Mirsky and Oshima (14) obtained results suggestive of the same localization of structures necessary to maintain this visual attention task. They produced irritative lesions by subcortical injection of aluminum cream and found that the integrity of the lower brain stem rather than the thalamus seemed to be crucial for maintaining the performance. The present study was designed to accomplish three purposes : (i) To replicate with more precision the earlier stimulation findings (13) ; (ii) to differentiate among subcortical areas whose manipulation is associated with distinctive types of errors in performance; and (iii) to differentiate between peripheral and central effects of stimulation so as to illuminate further the nature of centrally induced effects. METHODS Subjects: Experimental Situation. Five mature female Macaca mulatta monkeys served as subjects. During the experiments they were kept in a standard restraining chair. They also wore a tightly fitted jacket which limited their hand movement (for protection of devices attached to their head, tail, and arm) and which forced them to use the same (preferred) hand to perform the required response. An additional padded restraining device prevented excessive head movement during experimental sessions. At the conclusion of a day’s session animals were returned to their home cages. In the case of one subject only, it was necessary on several occasions to maintain the animal in the chair for a number of weeks. However, the animal tolerated the procedure well and remained in vigorous health during the study. The Tusk. The monkeys were trained to perform a rapidly presented serial color discrimination task, a version of the continuous performance test designed for human studies of visual attention by Rosvold et al. (20). In the present study, the animals worked within a dimly-lit testing booth and had to press a transilluminated 3.5 cm dia. response key (GrasonStadler 5704 B Digital Display) if the key was displaying a red (“positive”) stimulus. In the presence of blue or green (“negative”) stimuli, the subject had to withhold the response. Punishment (electric shock applied to the tail) was delivered if the animal did not press for the positive stimuli within the allowed time (omission error) or if it pressed

VISUALLY

COKTROLLED

BEHAVIOR

205

to the negative stimuli (commission error). The allowed avoidance time (i.e., red stimulus duration) was 1 set ; escape was possible for another second following shock onset. The tail shock was delivered through a Grason-Stadler E 6070 B shock generator at levels between 2 and 5 ma and for intervals of 1 sec. In general, the lowest level of shock that would sustain the behavior was utilized. The interstimulus interval was 5 sec. Szcrgery. After training was completed, the animals, under pentobarbital anesthesiahad an array of epidural guides ( 11) and epidural and subcortical recording electrodes implanted. The epidural recording electrode consisted of stainless steel machine screws of 4 mm diameter which were placed on the dura over the frontal, sensory-motor and occipital cortices. Pairs of screw electrodes constituted a bipolar cortical placement. The subcortical electrodes were concentric, consisting of stainless steel 26gauge tubing with a Teflon-insulated center wire of 0.127 mm cross section. The tube was insulated from the brain by Insul-X or Epoxylite, except for a 1 mm area at the tip. The center wire estended for about 2 mm beyond the tubing and its tip was bared of insulation for about 1 mm. The guides consisted of a 19-gauge stainless steel tubing 15 mm in length. They were inserted through burr holes in the skull so as to rest on the dura, and were cemented to the bone with acrylic cement. An array of 30 to 40 guides, separated from each other by 2.5 mm, was implanted bilaterally, anterior to the central sulcus. The boundaries of the area covered by the guide implant may be described by the following stereotaxic coordinates: posterior 4, lateral 12, anterior 12, 15, or 22, depending upon the subject. The stimulating electrodes or probes were similar to the subcortical recording electrodes described above. Sites of Probing. The probing was planned to include the following regions : thalamus, subthalamus; hypothalamus (caudal aspect) ; midbrain ; pons. Occasionally other sites such as the basal ganglia, cerebellum, hippocampal gyrus, and rostra1 part of the medulla were reached by the probing as a consequence of the individual deviation of the subject’s brain from the atlas standards. In one subject, systematic exploration of the head of the caudate nucleus was carried out; in another ,subject, cortical layers accessiblethrough the guides were also stimulated. Stimulating Methods; Testing Procedure. The constant current stimulation consisted of 100 Hz, 0.1 msec, monophasic positive pulses, ranging in intensity from 0.1 to 1.5 ma. The stimulation was delivered in trains of up to 50 set in length in the unanesthetized alert animal, during the administration of the task. In one animal, in addition to the 100 Hz stimulation, 3 Hz pulses of varied intensities were also applied parallel with the administration of the task. Moreover, brief trains (300-900 msec) of 100 Hz stimulation in varying intensities were occasionally used in all sub-

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jects, concurrently with the onset of task stimuli. Periods of nonstimulation alternated with periods of stimulation in a systematic way, to ensure the restoration of the baseline (control level of performance) following each stimulation epoch. The testing procedure consisted of the following steps: The dura was initially penetrated through the guide with a sterile hypodermic needle; the stimulating electrode was lowered (usually in 3 mm steps) ; every level was examined for its general behavioral effect (without administration of the task) and for the effects on the task produced by stimulation. Behaviorally effective points were examined further to establish the threshold of effective stimulation intensities and to define the topographical focus and boundaries of the effect. After the examination of a subject was complete (in 6-7 mo as an average), electrodes were cemented along the explored tracks at the level of the most significant effects. Subsequently, the animal was anesthetized with sodium pentobarbital anesthesia, and killed by pericardial perfusion of a saline-formalin mixture. The brain was prepared by conventional histological methods, cut in 40 ,prn sections and stained with cresyl violet and 1~x01 blue to facilitate the location of electrode tracks and tips. The stereotaxic atlas of the Macaca mulatta by Snider and Lee (22) was used for identification of points of interest in the brain. RESULTS Continuous Perforvnance Test Eflects. Electrical stimulation of the brain could induce three types of errors in the task : (i) Nonresponding to the positive stimulus (omission error) ; (ii) responding to the negative stimulus (commission error) ; and (iii) combinaton of these two errors (mixed error). Lack of any observable task was referred to as a “zero” effect.2 General Behavioral Effects. In addition to effects on the task, the stimulation often induced general behavioral effects, i.e., somatomotor and autonomic responses. These could vary from simple reflexive through more complicated, patterned behavioral sequences. The latter often had the appearance of motivated or emotional behavior. Only 76 (22%) out of the total of 353 points examined were free of any observable general behavioral effects. Some of these effects could be responsible for the impaired performance of the task on a peripheral basis by inducing motor responseswhich could interfere with carrying out the motor response required by the task, or by forcibly turning away the animal’s head and eye from the task stimuli. ZErrors could by elicited zero effect meant no errors used in this study (usually,

by less than maximal stimulation even when tested by the highest 100 Hz at 1.5 ma).

intensities; stimulation

however, a intensities

VISUALLY

CONTROLLED

207

BEHAVIOR

Such effects were eliminated from the analysis. The criteria for elimination differed somewhat according to the type of error. Presence of eye and head turn disqualified a point in all three types of errors. However, if an animal continued to perform correctly in spite of such somatomotor effects, the point was not eliminated from the category of a zero effect. Muscle activation in the working arm was considered disqualifying for omission error effects but not for commission error effects, on the basis of the following considerations : stimulation-induced activation of muscles would not produce a relatively complicated goal-directed response such as pressing the response key ; however, it may interfere with it and thus lead to omission errors on a peripheral basis. However, if in the presence of muscle activation, response to the key was possible and it was carried out during the presentation of the negative stimulus, it was concluded that the error was due to some central processes. On the basis of such considerations, 37 of the 353 points were excluded from further analysis. The general behavioral concomitant of the remaining 316 points, and their distribution according to the type of effect on the task, are presented in Table 1. There was no systematic relation between error type and general behavioral effect, except possibly for the high incidence of pain and aggression in conjunction with commission error effects; zero effects were often accompanied by eye and head turn and not infrequently by muscle contraction. Sleep or drowsiness was almost never observed in relation to stimulation. Occasionally, yawning was seen followTABLE RELATION

BETWEEN PERFORMANCE

General

behavioral

No effect Mild vague Eye & head Muscle

GENERAL TEST

EFFECTS

turn contraction

Pain & aggressionc Pupil change Arrest Miscellaneous Total

EFFECTS

PRODUCED

CPT

effect

effect*

1

BEHAVIORAL

OE

CE

11

8 27 0 0 30 2 3 2 72

25 0 0 3 6 4 6 55

AND

CONTINUOUS

BY STIMULATION

Effect

observeda

Mixed

Zero

0 5

Total

1 0

57 56 29 5

0

10

2 2

2 4 1.5 178

1 11

a CPT = Continuous Performance Test; OE = Omission Error; Mixed = OE + CE; Zero = No CPT Effect. * Including: Restlessness; mouthing; staring; mild muscle ing; yawning; grimacing; etc. c Including : Crying ; showing teeth ; slapping ; grabbing.

Error; tension;

76 113 30 5 43 12 13 24 316

CE

= Commission

blinking;

scratch-

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ET AL.

FIG. 1. Coronal sections through macaque brain showing locus of stimulation-induced effects on the Continuous Performance Test. Note the relative concentration of omission error points in the subthalamus and hypothalamus, mesencephalic, and pontine reticular formation and basal pons in contrast to the infrequent occurrence of this effect in the thalamus.

ing the stimulation, and in one case drowsiness followed the stimulationinduced eye-closure. Even spontaneous drowsiness seemed to be incompatible with the high frequency stimulation used in this study ; animals which would doze in the absence of the task or stimulation rarely did so during stimulation. Localization of Stindation Efects on the Continuous Performance Test: Continuous Long Trains. Of the 353 subcallosal points of stimulation obtained from five animals, 316 points were selected for further analysis, according to the previously described criteria. The anatomical localization of these points is represented in a series of seven coronal sections in Fig. 1. To facilitate visualization of the anterior-posterior distribution of the points, the majority of them are also represented in two sagittal sections in Fig. 2. Tables 2 and 3 summarize the information contained in these

I

*

’

VISIJALLY

14 12

IO 8

14 12 IO I III

8

6

6 I

4

CONTROLLED

2

0

2

4

6

8

10 12 14

4 2 III

0

2 I

4 I

6 I

8 I

10 12 14 I I I

209

BEHAVIOR

7J 8642o2-

W=

4-

X

68-

FIG.

OMISSION

ERROR

=

COMMISSION

=

MIXED

=

NO

ERROR

ERROR

EFFECT

1. Continued.

figures according to various anatomical criteria. Table 2 (which is comparable to Fig. 1) presents the distribution of the stimulation results by type of effect and by major anatomical subdivision. In the table, the effects observed in some adjacent regions were pooled in order to obtain categories with comparable numbers. Thus, the thalamic and subthalamic effects were pooled, the medullary effects were included in the pontine effects, and the cerebellar effects were included in the “other” category. Table 3 (which summarizes most of the information in Fig. 2) presents the distribution of stimulation effects by lateral distance from midline. The tables show that in almost half ( 138 of 316, or 44%) of the points, stimulation produced some kind of impairment of the task. The majority of the effects could be classified clearly as either omission error or commission error effects, the latter being somewhat more frequent than the former. Only a few cases (11 of 316, or 3.5%) fell in the mixed category.

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The anatomical location of the various task effects was not sharply delineated. Omission error, commission error, and zero effects were found in all regions, sometimes in close proximity to each other. However, it was possible to establish the predominant type of effect for each major anatomical subdivision. The region most affected by stimulation was the pons (and to a lesser extent the medulla), with 5 1 of 65, or 78% of the points yielding either omission error, commission error, or mixed effects (coronal map 4).3 The region least affected by stimulation was the thalamus in which only 19 of 88, or 22% of the points elicited errors (coronal maps l-4). The stimulation of the midbrain (coronal maps 3, 4, and 5) and subthalamic area and hypothalamus (coronal maps 1 and 2) was moderately effective with 39 of 67, or 58% and 14 of 28, or 50% combined errors, respectively. The high proportion of ineffective points in the “other” category was due to the lack of effect seen in the head of the caudate nucleus (coronal maps 1 and 2)) the anterior cerebellum (coronal map 7) and ventricles. The proportion of behaviorally effective points for this group was 5 out of 36 or 14%. In general, omission errors occurred more frequently in medial locations, whereas commission errors were more common in lateral regions (Table 3, Fig. 2). Thus, in the thalamus, three out of the four omission error points fell in the midline nuclei (MD, Pf ; see coronal maps 2 and 4) while ten out of 13 commission error effects fell into more laterally situated nuclei (VPL, VPM, VL, LD ; see coronal maps l-4). Eight of these were also located posteriorly. In contrast, the heaviest concentration of ineffective points was in the anterior part of the thalamus (sagittal map 1). The subthalamus and hypothalamus were the site of predominantly omission error effects in contrast to the thalamus in which few such points were observed (coronal maps 1 and 2). Part of these omission error effects were found in the mamillary region (coronal maps 1 and 2) and part in 3In the coronal maps, all task effects are indicated on the right side of the brain, aithough they may ha* been derived from stimulation of either the left or the right side. FIG. 2. Sagittal sections of macaque brain showing location of stimulation-induced effects of the Continuous Performance Test. Note the concentration of omission error points in the more medial section of the lower brain stem as compared to the concentration of commission error points in the more lateral section of the brain. Commission errors are seen to cluster in the thalamus, mesencephalic tectum, and around the trigeminal system of the lower brainstem. See legend to Fig. 1 for code of behavioral effects. The following abbreviations are used in addition to those in Table 4: AC = anterior commissure; OCH = optic chiasm; CC = corpus callosum; MED = medulla oblongata; TH = thalamus; IC = internal capsule.

VISUALLY

10-I

Lot

CONTROLLED

211

BEHAVIOR

1.0-4.0

15I

I 20

I 15

I 10

I 5

I 0

I 5

I 10

I 15

I

I

I

I

I

I

I

I

20

15

10

5

0

5

10

15

I 20

15i520

212

BAKAY

PRAGAY TABLE

DISTRIBUTION

2

OF STIMULATION-INDUCED CONTINUOUS EFFECTS BY LOCATION OF POINTS WITHIN STRUCTURAL SUBDIVISIONF

Region

CPT

Thafamus Sub- and hypothalamus Midbrain Pons and medulla Otherc Total a Table b OE = c Other ventricles

ET AL.

Effect

OE

CE

Mixed

6 8 13 20 8 55

13 4 22 27 6 72

0 2 4 4 1 11

PERFORMANCE MAJOR

TEST

observedb Zero

Total error points 19 14 39 51 1.5 138

entries refer to number of points where given effects Omission error; CE = Commission error. includes: Cerebellum; caudate nucleus; internal ; extracerebral space ; globus pallidus ; optic tract.

were

Total points

69 14 28 14 53 178

88 28 67 6.5 68 316

induced.

capsule;

hippocampus;

the nucleus subthalamicus (coronal map 2). The subthalamic nucleus was the only laterally situated region in which a substantial number of omission error effects were seen. The central part of the midbrain tegmentum (including the MRF, central gray, red nucleus and area pretectalis) contained the majority (ten out of 13) of the omission error effects seen in the midbrain. Very few of the commission error effects (four of 22) were seen here (coronal maps 3 and 4 and sagittal map 1). On the other hand the tectum (including the superior and inferior colliculi) and central-lateral midbrain (inTABLE DISTRIBUTION

3

OF CONTINUOUS PERFORMANCE TEST EFFECTS LATERAL DISTANCE FROM MIDLINE CPT

Lat. 1.0-4.0 Lat. 4.5-6.5 Lat. 7.0-12.0 Total 6 OE

= Omission

error;

Effect

BY

Observeda

OE

CE

Mixed

Total error points

Zero

Total points

41 11 3 55

28 38 6 72

6 5 0 11

75 54 9 138

94 62 22 178

169 116 31 316

CE

= Commission

error.

VISUALLY

CONTROLLED

BEHAVIOR

213

eluding the cerebral peduncle and the substantia nigra) were the site of the majority of the commission error (14), but relatively few (2) of the omission error points (coronal maps 3, 5, and 6 and sagittal map 1). These latter subdivisions also contained the majority of the zero effects (18 out of the total of 27 zero effects as compared to three such effects in the tegrnental part). The midline pons including both the dorsal (tegmental) and the ventral (basal) aspects were characterized by a large concentration of omission error effects (17 out of 20 pontine omission error effects were found here). However, the tegmental area of the pons contained also a considerable number of commission error effects ; 19 out of the total of 27 commission error effects were found here (sagittal map 1). Only one commission error effect was found in the basal part. The lateral aspect of the pons produced few omission error effects and numerous commission error effects (three omission errors vs. 13 commission errors: sagittal map 2) ; 11 out of the total of 27 pontine commission error effects were found to be associated with ascending specific sensory systems (lateral lemniscus, medial lemniscus, facial, vestibular and trigeminal nerves, and nuclei). Since some of these pathways run medially at the pontine level, the dichotomy seen in other areas (medial = omission error vs. lateral = commission error) is not entirely applicable to this region. For this region with its closely related and often interwoven structures and pathways, a classification by functional rather than topographic characteristics offers the best separation of the task effects. Thus, it appears that the majority of the omission error effects were related to nonspecific nuclear masses (nuclei of the pontine reticular formation, tegmental nuclei, pontine nuclei) and nonspecific ascending pathways (central tegmental tract), whereas the majority of the commission error effects were associated with specific sensory pathways, cranial nerves, and nuclei. Task Effects with Brief Trains of Stimulation,. Brief trains of stimulation applied at the onset of the task stimuli (“onset” stimulation) were administered in addition to the long train (“continuous” stimulation) at 46 points. This type of stimulation was especially effective in inducing omission errors. In 24 cases, points which produced zero effects with continuous stimulation now elicited errors with onset stimulation; 79% of these were omission errors. In four instances, commission error effects became omission error effects when continuous stimulation was replaced by onset stimulation. There was no example of the opposite type of change. Changes from zero or commission error effect into omission error effect occurred in several regions. The omission error effect due to onset stimulation was more widely distributed than that due to continuous stimulalation; it was seen in regions with a high density of omission errors with

214

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TABLE ABBREVIATIONS AM AV Br. col. s Br. conj Br. pont Ca. int Caud Cereb CG Cn. Md Col. i Cal. s co. p Dec. Br. con Forn HZ Hab HYP LA LD L. gen LL LP Mam MD M. gen ML MRF N. III N. V. sn. pr N. VI N. VIII 01. inf 01. s Pal Fed Pf PRF Pul. i Pul. 0 Put P yr R Re Rub SG Subt. nigr, SN

ET AL.

4

USED IN ILLUSTRATIONS nucleus (n.) anterior medialis n. anterior ventralis brachium colliculi superioris brachium conjunctivum brachium pontis capsula interna n. caudatus cerebellum griseum centrale n. centrum medianum colliculus inferior colliculus superior commissura posterior decusatio brachiorum conjunctivarum fornix Forel’s field Hz n. habenularis hypothalamus lobus anterior cerebelli n. lateralis dorsalis corpus geniculatum laterale lemniscus lateralis n. lateralis posterior corpus mamillare n. medialis dorsalis corpus geniculatum mediale lemniscus medialis formatio reticularis mesencephali n. nervi oculomotorii n. nervi trigemini sensibilis princip. n. nervi abduncentis n. nervi acustici oliva inferior oliva superior n. pallidus pes pedunculi n. parafascicularis formatio reticularis pontis n. pulvinaris inferior n. pulvinaris oralis putamen tractus pyramidalis n. reticularis n. reuniens n. ruber n. suprageniculatus substantia nigra

VISUALLY

CONTROLLED

TABLE Subth TrII Tr. hbip VA VLm VLO VPM VPL Zic IV VII

BEHAVIOR

215

4 (continued) n. subthalamicus Luysi tractus opticus tractus habenulo interpeduncularis n. ventralis anterior n. ventralis lateralis, pars medialis n. ventralis lateralis, pars oralis n. ventralis posterior medialis n. ventralis posterior lateralis zona incerta nervus trochlearis nervus facialis

continuous stimulation (mesencephalic reticular formation and pontine reticular formation) as well as in areas with low or zero density of omission errors with continuous stimulation (thalamus, head of the caudate nucleus). Low Frequency Stiwdation. In one subject, every explored point was tested both with high frequency (100 Hz) and low frequency (3 Hz) stimulation of varied intensity. The 3 Hz stimulation sometimes induced rhythmic twitching of muscles in areas where high frequency stimulation would induce sustained muscle tension. However, the 3 Hz stimulation was virtually without effect on the task performance. Stimulation of the Cortex. High frequency (100 Hz) moderate intensity stimulation was applied at various levels of the somatosensory cortex in one subject. Stimulation of the gray matter often induced generalized tonic-clonic seizures which usually outlasted the stimulation, Task performance was severely suppressed during and immediately following seizure activity; during the recovery period from the postseizure lull, mixed effects, and sometimes predominantly commission error effects were observed. Except for the seizures and their consequent effect on performance, stimulation of the cortex (and also the adjacent corpus callosum) was largely without effect on general behavior and on the continuous performance test. DISCUSSION The present results confirm the findings of Mirsky and Oshima (14) and the stimulation effects cited in Mirsky and Orren (13). Experimental manipulation of the brain stem is more disruptive of the continuous performance test than is that of the thalamus. The present data also indicate a functional-topographic separation of various kinds of task errors. This

216

BAKAYPRAGAYETAL.

separation encourages the discussion of these effects as different classesof phenomena. The anatomical location of the regions where stimulation elicited omission errors are all part of the mesopontine reticular formation or structures which are anatomically and functionally related to it. In contrast, the regions in which stimulation induced commission errors are primarily located in or closely adjacent to specific sensory systems. Those regions in which the majority of omission errors were elicited are interconnected with each other by efferent pathways. Those regions of the diencephalon in which omission errors were produced (posterior hypothalamus, nucleus subthalamicus) as well as the basal pons have direct or indirect efferent pathways projecting to the mesopontine tegmentum. On the basis of relevant literature (8, 21, 24) it may be assumed that the posterior hypothalamic effect is functionally equivalent to the activating effect seen with the stimulation of the reticular formation proper; in the case of the subthalamus and the basal pons, the connections may be part of the descending extrapyramidal pathways converging upon the mesopontine reticular formation which is thought to be important in sensory-motor integration. Direct stimulation of the reticular formation may lead to omission errors by various mechanisms: (i) distraction, i.e., by evoking specific sensations which compete with or mask the task stimuli ; (ii) general deactivation of the cortex by stimulating so-called sleep-centers; (iii) general hyperactivation of the cortex, resulting from the excitation of the diffuse activating system, and eventuating in disturbance of visual reception and/or motor output; (iv) motor inhibition at subcortical levels by mobilization of the descending inhibitory system; (v) specific inhibition of sensory (visual) input by “gating” through tegmentofugal efferents projecting to various levels of the visual system; (vi) m * ter ference with normal ascending activating processes; and (vii) interruption of some visual-motor integrating circuits and/or some motor coordinating feedback mechanisms within the reticular formation, as it is interconnected with cerebellar and other extrapyramidal regulatory systems. It may be noted that the first five mechanisms listed above represent mobilization of the normal function of the reticular formation which may lead to errors by being excessive or by being out of place with respect to the phases of the task: on the other hand, the last two mechanismsinvolve local interference with the functions of the reticular formation in the senseof a “reversible lesion.” The present results do not permit an exact determination of the mechanisms underlying omission errors. However, some of the aforementioned alternatives may be eliminated on the basis of the following considerations: high frequency stimulation of the reticular formation does have cue properties; it may serve as a conditioned stimulus even at rather low in-

VISUALLY

CONTROLLED

BEHAVIOR

217

tensities (1.5). Thus it may represent a distracting input in the present context. However such effects are more likely to be present with brief trains of stimulation applied in parallel with task stimulus onset rather than with long trains of continuous stimulation as used in the present study. The finding that “onset” stimulation was more effective in inducing errors and especially omission errors in many areas (among them the mesopontine reticular formation) may represent the distracting effect of “onset” stimulation as compared to the less effective “continuous” stimulation. Deactivation may be ruled out on the basis of the general behavioral observations; sleep or drowsiness was almost never observed to accompany the high frequency stimulation used in this study. General motor inhibition (arrest) could be responsible for the omission errors in a restricted number of cases. However, since motor arrest of ongoing behavior did not necessarily lead to omission errors in the task (Table l), it seems unlikely that significant number of omission errors can be attributed simply to motor arrest. The elimination of these alternatives focuses attention on the ascending activating and the local integrative functions of the reticular formation. It is well known that activation of the cortex may have behavioral consequences in terms of a shift along the sleep-wakefulness continuum. A shift from drowsiness to alert wakefulness appears to be facilitatory in a wide range of task performances. Less clear are the behavioral effects of the activating stimulation of the already alert wakeful subject. Facilitatory effects (4-6, 26) as well as inhibitory (impairing) effects (9, 18) of high frequency stimulation of the reticular formation have been reported both on learning and performance of various tasks. Grastyin, Lissik, and Kekesi (7) reported inhibition of an alimentary and facilitation of a defensive conditioned reflex obtained from the stimulation of the same reticular formation point ; Sterman and Fairchild (23), Wilson and Radloff (25)) and Eliasson and Kornetsky (3) reported differential effects as a function of stimulation intensity, low intensities being facilitatory, higher intensities being inhibitory. A conceptual framework which could be applied to these data is the inverted U hypothesis (2, 10, 12). According to this view, the impairing effect of the activating stimulation results from a hypothetical higher-than-optimal level of arousal. In principle, such a state might have resulted from the high frequency stimulation that was applied in the present study to the awake alert animal. Indirect evidence of such a state was provided by Kornetsky and Eliasson (9)) and Eliasson and Kornetsky (3) who demonstrated that a tranquilizing drug (chlorpromazine), which by itself causes behavioral impairment through cortical deactivation, would reverse the detrimental effect of “hyperarousing” stimulation. Direct evidence of cortical hyperarousal was provided by Pass (17), who found increased fast activity in the cortex following reticular formation stimulation with the same parameters and

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methods which were used by Kornetsky and Eliasson. However, the mechanism leading to erroneous behavior on the basis of cortical hyperarousal remains to be defined. One of the possible mechanisms underlying omission errors during cortical hyperarousal may be the excessive gating of sensory input. Sensory gating, one of the many regulatory mechanisms of the reticular formation, is thought to be adaptive under normal conditions. However, under pathological conditions it may lead to erroneous behavior; attenuation of evoked potential amplitude was found to be associated with impaired performance in some subjects with petit ma1 epilepsy (16). The effects of electrical stimulation on sensory transmission in relation to performance was assessed in these animals by the evoked method; we will report these results in a separate communication. Commission errors in the continuous performance test may be cognitivevs. disinhibition). The associative or dynamic in nature (i.e., “confusion” dynamic or even specific-motivational character of the commission error effects encountered here is suggested by general behavioral data as well as by functional-anatomical information. In a large number of instances, commission errors were accompanied by evidence of pain, distress, or hostility, while in only a few instances were omission errors and zero effects accompanied by such manifestations (Table 1). Spontaneous intertrial responding as well as multiple commission errors (repeated pressing of the response key) in the presence of negative stimuli were encountered frequently. The stimulation-induced diffuse hitting-grabbing movements seen outside the test situation could well be subsumed within the erroneous and excessive key-pressing behavior seen during the task. This kind of behavior differs obviously from the barbiturate-induced “confusion” which oftens leads to mixed omission error-commission error effects (1). The areas from which most commission errors were elicited (trigeminal system, midbrain tectum, posterolateral thalamus) have known somatosensory or even specific pain-conveying functions. [A somatosenory area in the tectum was recently described by Robards, Watkins, and Masterton (19) 1. Although the specific pain effect is inevitably associated with nonspecific activation via collateral connections, the fact that direct stimulation of the reticular formation did not often lead to commission errors suggests that the specific sensory effect is a necessary component of the commission errors under the present conditions. REFERENCES 1. BAKAY PRAGAY, E., A. F. MIRSKY, and J. ABPLANALP. 1969. The effects of Chlorpromazineand secobarbital on matching from sample and discrimination tasks in monkeys. Psychopharmacologia (Berlin) 16 : 128-138. 2. DUFFY, E. 1957. *he psychological significance of the concept of “arousal” or “activation”. Psychol. Rev. 64 : 265-275.

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