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An hypothesis on the mechanism of cortical recruiting responses
208
BRAIN RESEARCH
AN H Y P O T H E S I S ON T H E M E C H A N I S M OF C O R T I C A L R E C R U I T I N G RESPONSES*
J. D. S C H L A G , R. L. K U H N
AND
M. VELASCO**
Departments of Anatomy and Physiology, and Brain Research Institute, University of California Los Angeles, Calif. (U.S.A.) (Received December 3rd, 1965)
INTRODUCTION
Velasco and Lindsley 9 recently showed that the surgical removal of the 0rbitofrontal cortex in cats completely eliminated cortical and subcortical recruitihg responses previously induced by low-frequency stimulation of midline or intralaminar thalamic nuclei. As the removal of any other parts of the cerebral mantle - - regardless of extent - - was comparatively ineffectual, this result suggests the existence of a rather localized system of thalamo-cortical projections. Such an hypothesis, first formulated by Rose and Woolsey 4-6, was later supported by N a u t a and Whitlock a on the basis of degeneration studies. The present experiments were designed (1) to determine if stimulation of midline or intralaminar thalamic nuclei would elicit short-latency responses in the orbitofrontal region, and (2) to investigate the relation of such responses with the classical surface-negative recruiting responses found broadly distributed all over the lateral surface of the brain. METHODS
In 14 cats, operated on under ether and local anesthesia, and later immobilized with Flaxedil, the anterior half of the cerebral cortex was exposed, and kept under a pool of warm mineral oil. In three cases, the frontal pole of one hemisphere was sucked out in order to have access to the medial face of the other under visual control. Trains of 0.5 msec, 2 to 6 V square pulses were administered at a rate of 10/sec through fine concentric electrodes to different points of the midline and intralaminar nuclei (nuclei centralis medialis, N C M ; reuniens, Re; paracentralis, Pc; and centralis lateralis, CL; as verified on histological sections). For control purposes, nuclei ventralis lateralis (VL), ventralis posterolateralis (VPL), and medialis dorsalis (MD) * Supported by grant NB-04955 from NIH. ** Present address: Division of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Md.
(U.S.A.). Brain Research, 2 (1966) 208-212
209
RECRUITING RESPONSES
were sometimes stimulated in the same conditions. Ipsilateral cortical potentials were derived either bipolarly (between surface and underlying white matter) or monopolarly (between surface and a remote reference electrode). Polarities indicated in the results are those of cortical surface leads. R ESU LTS
In each animal the recruiting responses elicited on the anterior and posterior sigmoid, lateral and suprasylvian gyri had no initial surface-positivity and their latency was at least 25 msec. It was found that such recruiting responses were always accompanied by initial positive potentials in the ipsilateral orbitofrontal region, as illustrated in Fig. 1A and C. There were two types of positive potentials. The earliest ones occurred in 3 to 5 msec and their amplitude remained constant or decreased slightly with repetition at 10/sec. The second type (Fig. IC) had a latency of 15 to 20 msec, was small or absent after the first stimulus but increased with the following ones. Each type could be seen separately while recording from cortical points separated by a few millimeters but generally they appeared in succession in the same record.
200 msec
a m l a m
50 m sec
E
i ")OOrnse¢
Fig. I. Records from anterior sigmoid gyrus (S) and orbital region (O, external bank of presylvian sulcus) during 10/sec stimulation. Surface-negativity upwards. N C M stimulation in A and C, VL stimulation in B and D, all in the same cat. A and B: continuous recordings. C and D : upper pairs show responses to first stimulus, lower pairs to fifth stimulus of the train. E: stimulation of orbitofrontal region of medial wall in a different animal. Voltage calibrations: 250 #V.
Both showed reversal in the deep cortical layers. The n u m b e r of observations made was insufficient to determine accurately the distribution of the two types of initial positive responses, especially as the cortical surfaces explored could not ordinarily be seen in their entirety. Besides, this distribution was found to vary with the thalamic placements. With the most lateral positions (e.g. CL) - - which were those inducing recruiting responses on the posterior parts of the cortex (on the suprasylvian and lateral gyri) - - the initial positive responses were detected most often on the medial wall of the hemispheres, whereas with midline positions (e.g. Re or N C M ) - - inducing reBrain Research, 2 (1966)208-212
210
J.D. SCHLAG, R. L. KUHN AND M. VELASCO
cruiting responses predominant in the perisigmoid area - - positive responses could be obtained from the orbital as well as from the medial face of the frontal pole. Cortical foci of initial positive responses were situated on the external bank of the presylvian sulcus and at the limit, of the medial orbitofrontal and anterior limbic region (according to Rose and Woolsey's mapping of the medial wallS). Quite generally, both types of initial positive deflections were followed by a large negative potential. The one following the longer-latency positive deflection was particularly interesting because it occurred exactly in phase with the negative recruiting responses simultaneously recorded on the perisigmoid, lateral or suprasylvian gyri (Fig. 1A and C). It developed progressively and then declined with repetition of the stimuli and exhibited the typical waxing and waning of recruiting responses; it was easily suppressed by any kind of arousing stimulation. The description given here of orbitofrontal responses to 'recruiting' midline or intralaminar stimulation corresponds more closely to typical 'augmentation' than to typical 'recruitment'. For the purpose of comparison, the VL or VPL nuclei were stimulated at the same 10/sec frequency while recording from the perisigmoid and adjacent areas. Two types of initial positive responses were seen: respectively, the 1.5 to 2 msec latency 'specific' response, decreasing with repetition, and narrowly localized; and the l0 msec latency 'augmenting' response, increasing with repetition and more broadly distributed on the perisigmoid region (Fig. I B and D). Longlatency, initial negative responses were regularly obtained at the periphery of the surface-positive foci, that is on the lateral, suprasylvian and orbitofrontal areas. The similarity of the cortical effects obtained by repetitive stimulation of either NCM, Re, Pc or VL, VPL was stressed in five experiments by performing both stimulations in succession and recording from the same cortical points (orbital and sigmoid areas). The initial positive responses appeared at one of the places and the initial long-latency negative responses at the other (Fig. 1A, B, C and D). There was a remarkable reciprocity, even though the latencies of the various components were of a definitely different order of magnitude. In order to analyze the mechanism of elicitation of negative potentials, which so regularly were found in regions surrounding foci of initial positive responses, the latter foci were directly stimulated transcortically (anode at the surface, cathode l to 2 mm within the cortex). These stimulations resulted in negative potentials developing in 2 msec or less; their cortical distribution and relative amplitude corresponded to that of thalamically induced recruiting responses, provided that the cortical stimulation be carried out at the exact place where initial positive responses could be detected following the thalamic stimuli (Fig. I E). Repetitive stimulations of the same orbitofrontal points elicited longer-latency negative potentials, progressively increasing, waxing and waning and mimicking true "recruiting" responses. DISCUSSION The relevance of comparing the orbitofrontal responses described here and the simultaneously recorded recruiting responses may be questioned on the ground that Brain Research, 2 (1966)208-212
RECRUITING RESPONSES
211
these phenomena may have different anatomical origins. The positive orbitofrontal responses may be due to the stimulation of structures close to but distinct from the intralaminar or midline nuclei. Indeed, the mediodorsaI nucleus is known to project directly to the orbitofrontal area and the anterior nucleus group to the limbic cortexS,~. Thus, the simultaneous elicitation of recruiting responses and short-latency orbitofrontal responses might be pure coincidence due to simultaneous stimulation of neighboring nuclei. It should be noted however (1) that this coincidence was encountered in all 14 experiments performed, without exception, (2) that it extended up to a perfect correspondence between the Iatencies of the monophasic negative recruiting responses and of the late negative component of the orbitofrontal responses, and (3) that both recruiting responses and late negative components evolved in parallel on repetitive stimulation. Also noteworthy was the finding of a similar relation between the late negative component of sigmoid augmenting responses and monophasic negative orbitofrontaI responses. Therefore, the possibility should be considered that negative cortical potentials tend to develop secondarily in and around any focus activated by a strong and well synchronized excitation. This hypothesis is worth exploring though the thalamic structures responsible for the orbitofrontal potentials disclosed have not been satisfactorily determined yet. The important point is that recruitment may be explained as a secondary effect. Generalized recruitment probably depends on particular thalamo-orbitofrontal projections, but more localized recruiting or 'recruiting-like' responses may also be obtained by various kinds of thalamic stimulations. In all these cases, it can be conceived that the spread of late negative potentials on the cerebral cortex is due to an organization of lateral inhibition or excitation, the existence cf which has been postulated at the thalamic I and cortical levels z,7,s. Such a possibility is now under investigation. SUMMARY
Repetitive stimulation of midline and intralaminar thalamic nuclei produced initial positive responses in the orbital region of the cat's cerebral cortex. In the same region, long latency monophasic negative responses were evoked by repetitive stimulation of the specific relay nucleus to the cortical sensori-motor area. 'Augmentinglike' and 'recruiting-like' responses could readily be found concomitantly, when recording from the proper places, regardless of whether 'specific' or 'unspecific' thalamic nuclei were stimulated. The main significant differences were latency and cortical distribution.
REFERENCES
I ANDERSEN,P., ECCLES, J. C., AND SEARS, T. A., The ventro-basal complex of the thalamus: types of cells, their responses and their functional organization, J. PhysioL, 174 (1964) 370-399. 2 ASANUMA, H., AND BROOKS, V. B., Recurrent cortical effects following stimulation of internal capsule, Arch. itaL Biol., 103 (1965)220-246. 3 NAUTA, W. J. H., AND WHITLOCK, D. G., An anatomical analysis of the non-specific thalamic
Brain Research, 2 (1966) 208-212
212
J . D . SCHLAG, R. L. KUHN AND M. VELASCO
projection system. In J. F. DELAFRESNAYE (Ed.), Brain Mechanisms and Consciousne,'s, Blackwell, Oxford, and Masson, Paris, 1954, p. 81. 4 RosE, J. E., AND WOO~EY, C. N., A study of thalamo-cortical relations in the rabbit, Bull. Johns Hopkins Hosp., 73 (1943) 65-128. 5 RosE, J. E., AND WOOLSEY, C. N., Structure and relations of limbic cortex and anterior thalamic nuclei in rabbit and cat, J. comp. NeuroL, 89 (1948) 279-340. 6 ROSE, J. E., AND WOOLSEY, C. N., The orbitofrontal cortex and its cormections with the mediodorsal nucleus in rabbit, sheep and cat, Res. PubL Ass. nerv. ment. Dis., 27 (1948) 210-232. 7 SCHLAG, J., Reactions and interactions to stimulation of the motor cortex of the cat, J. Neurophysiol., in press. 8 Sa'~:FANIS, C., ANt> JASPER, H., Recurrent collateral inhibition in pyramidal tract neurons, J. Neurophysiol., 27 (1964) 855-877. 9 VEL~CO, M., AND LXNDSLEY,D. B., Role of orbital cortex in regulation of thalamocortical electrical activity, Science, 149 (1965) 1375-1377.
Brain Research, 2 (1966) 208-212
BRAIN RESEARCH
AN H Y P O T H E S I S ON T H E M E C H A N I S M OF C O R T I C A L R E C R U I T I N G RESPONSES*
J. D. S C H L A G , R. L. K U H N
AND
M. VELASCO**
Departments of Anatomy and Physiology, and Brain Research Institute, University of California Los Angeles, Calif. (U.S.A.) (Received December 3rd, 1965)
INTRODUCTION
Velasco and Lindsley 9 recently showed that the surgical removal of the 0rbitofrontal cortex in cats completely eliminated cortical and subcortical recruitihg responses previously induced by low-frequency stimulation of midline or intralaminar thalamic nuclei. As the removal of any other parts of the cerebral mantle - - regardless of extent - - was comparatively ineffectual, this result suggests the existence of a rather localized system of thalamo-cortical projections. Such an hypothesis, first formulated by Rose and Woolsey 4-6, was later supported by N a u t a and Whitlock a on the basis of degeneration studies. The present experiments were designed (1) to determine if stimulation of midline or intralaminar thalamic nuclei would elicit short-latency responses in the orbitofrontal region, and (2) to investigate the relation of such responses with the classical surface-negative recruiting responses found broadly distributed all over the lateral surface of the brain. METHODS
In 14 cats, operated on under ether and local anesthesia, and later immobilized with Flaxedil, the anterior half of the cerebral cortex was exposed, and kept under a pool of warm mineral oil. In three cases, the frontal pole of one hemisphere was sucked out in order to have access to the medial face of the other under visual control. Trains of 0.5 msec, 2 to 6 V square pulses were administered at a rate of 10/sec through fine concentric electrodes to different points of the midline and intralaminar nuclei (nuclei centralis medialis, N C M ; reuniens, Re; paracentralis, Pc; and centralis lateralis, CL; as verified on histological sections). For control purposes, nuclei ventralis lateralis (VL), ventralis posterolateralis (VPL), and medialis dorsalis (MD) * Supported by grant NB-04955 from NIH. ** Present address: Division of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Md.
(U.S.A.). Brain Research, 2 (1966) 208-212
209
RECRUITING RESPONSES
were sometimes stimulated in the same conditions. Ipsilateral cortical potentials were derived either bipolarly (between surface and underlying white matter) or monopolarly (between surface and a remote reference electrode). Polarities indicated in the results are those of cortical surface leads. R ESU LTS
In each animal the recruiting responses elicited on the anterior and posterior sigmoid, lateral and suprasylvian gyri had no initial surface-positivity and their latency was at least 25 msec. It was found that such recruiting responses were always accompanied by initial positive potentials in the ipsilateral orbitofrontal region, as illustrated in Fig. 1A and C. There were two types of positive potentials. The earliest ones occurred in 3 to 5 msec and their amplitude remained constant or decreased slightly with repetition at 10/sec. The second type (Fig. IC) had a latency of 15 to 20 msec, was small or absent after the first stimulus but increased with the following ones. Each type could be seen separately while recording from cortical points separated by a few millimeters but generally they appeared in succession in the same record.
200 msec
a m l a m
50 m sec
E
i ")OOrnse¢
Fig. I. Records from anterior sigmoid gyrus (S) and orbital region (O, external bank of presylvian sulcus) during 10/sec stimulation. Surface-negativity upwards. N C M stimulation in A and C, VL stimulation in B and D, all in the same cat. A and B: continuous recordings. C and D : upper pairs show responses to first stimulus, lower pairs to fifth stimulus of the train. E: stimulation of orbitofrontal region of medial wall in a different animal. Voltage calibrations: 250 #V.
Both showed reversal in the deep cortical layers. The n u m b e r of observations made was insufficient to determine accurately the distribution of the two types of initial positive responses, especially as the cortical surfaces explored could not ordinarily be seen in their entirety. Besides, this distribution was found to vary with the thalamic placements. With the most lateral positions (e.g. CL) - - which were those inducing recruiting responses on the posterior parts of the cortex (on the suprasylvian and lateral gyri) - - the initial positive responses were detected most often on the medial wall of the hemispheres, whereas with midline positions (e.g. Re or N C M ) - - inducing reBrain Research, 2 (1966)208-212
210
J.D. SCHLAG, R. L. KUHN AND M. VELASCO
cruiting responses predominant in the perisigmoid area - - positive responses could be obtained from the orbital as well as from the medial face of the frontal pole. Cortical foci of initial positive responses were situated on the external bank of the presylvian sulcus and at the limit, of the medial orbitofrontal and anterior limbic region (according to Rose and Woolsey's mapping of the medial wallS). Quite generally, both types of initial positive deflections were followed by a large negative potential. The one following the longer-latency positive deflection was particularly interesting because it occurred exactly in phase with the negative recruiting responses simultaneously recorded on the perisigmoid, lateral or suprasylvian gyri (Fig. 1A and C). It developed progressively and then declined with repetition of the stimuli and exhibited the typical waxing and waning of recruiting responses; it was easily suppressed by any kind of arousing stimulation. The description given here of orbitofrontal responses to 'recruiting' midline or intralaminar stimulation corresponds more closely to typical 'augmentation' than to typical 'recruitment'. For the purpose of comparison, the VL or VPL nuclei were stimulated at the same 10/sec frequency while recording from the perisigmoid and adjacent areas. Two types of initial positive responses were seen: respectively, the 1.5 to 2 msec latency 'specific' response, decreasing with repetition, and narrowly localized; and the l0 msec latency 'augmenting' response, increasing with repetition and more broadly distributed on the perisigmoid region (Fig. I B and D). Longlatency, initial negative responses were regularly obtained at the periphery of the surface-positive foci, that is on the lateral, suprasylvian and orbitofrontal areas. The similarity of the cortical effects obtained by repetitive stimulation of either NCM, Re, Pc or VL, VPL was stressed in five experiments by performing both stimulations in succession and recording from the same cortical points (orbital and sigmoid areas). The initial positive responses appeared at one of the places and the initial long-latency negative responses at the other (Fig. 1A, B, C and D). There was a remarkable reciprocity, even though the latencies of the various components were of a definitely different order of magnitude. In order to analyze the mechanism of elicitation of negative potentials, which so regularly were found in regions surrounding foci of initial positive responses, the latter foci were directly stimulated transcortically (anode at the surface, cathode l to 2 mm within the cortex). These stimulations resulted in negative potentials developing in 2 msec or less; their cortical distribution and relative amplitude corresponded to that of thalamically induced recruiting responses, provided that the cortical stimulation be carried out at the exact place where initial positive responses could be detected following the thalamic stimuli (Fig. I E). Repetitive stimulations of the same orbitofrontal points elicited longer-latency negative potentials, progressively increasing, waxing and waning and mimicking true "recruiting" responses. DISCUSSION The relevance of comparing the orbitofrontal responses described here and the simultaneously recorded recruiting responses may be questioned on the ground that Brain Research, 2 (1966)208-212
RECRUITING RESPONSES
211
these phenomena may have different anatomical origins. The positive orbitofrontal responses may be due to the stimulation of structures close to but distinct from the intralaminar or midline nuclei. Indeed, the mediodorsaI nucleus is known to project directly to the orbitofrontal area and the anterior nucleus group to the limbic cortexS,~. Thus, the simultaneous elicitation of recruiting responses and short-latency orbitofrontal responses might be pure coincidence due to simultaneous stimulation of neighboring nuclei. It should be noted however (1) that this coincidence was encountered in all 14 experiments performed, without exception, (2) that it extended up to a perfect correspondence between the Iatencies of the monophasic negative recruiting responses and of the late negative component of the orbitofrontal responses, and (3) that both recruiting responses and late negative components evolved in parallel on repetitive stimulation. Also noteworthy was the finding of a similar relation between the late negative component of sigmoid augmenting responses and monophasic negative orbitofrontaI responses. Therefore, the possibility should be considered that negative cortical potentials tend to develop secondarily in and around any focus activated by a strong and well synchronized excitation. This hypothesis is worth exploring though the thalamic structures responsible for the orbitofrontal potentials disclosed have not been satisfactorily determined yet. The important point is that recruitment may be explained as a secondary effect. Generalized recruitment probably depends on particular thalamo-orbitofrontal projections, but more localized recruiting or 'recruiting-like' responses may also be obtained by various kinds of thalamic stimulations. In all these cases, it can be conceived that the spread of late negative potentials on the cerebral cortex is due to an organization of lateral inhibition or excitation, the existence cf which has been postulated at the thalamic I and cortical levels z,7,s. Such a possibility is now under investigation. SUMMARY
Repetitive stimulation of midline and intralaminar thalamic nuclei produced initial positive responses in the orbital region of the cat's cerebral cortex. In the same region, long latency monophasic negative responses were evoked by repetitive stimulation of the specific relay nucleus to the cortical sensori-motor area. 'Augmentinglike' and 'recruiting-like' responses could readily be found concomitantly, when recording from the proper places, regardless of whether 'specific' or 'unspecific' thalamic nuclei were stimulated. The main significant differences were latency and cortical distribution.
REFERENCES
I ANDERSEN,P., ECCLES, J. C., AND SEARS, T. A., The ventro-basal complex of the thalamus: types of cells, their responses and their functional organization, J. PhysioL, 174 (1964) 370-399. 2 ASANUMA, H., AND BROOKS, V. B., Recurrent cortical effects following stimulation of internal capsule, Arch. itaL Biol., 103 (1965)220-246. 3 NAUTA, W. J. H., AND WHITLOCK, D. G., An anatomical analysis of the non-specific thalamic
Brain Research, 2 (1966) 208-212
212
J . D . SCHLAG, R. L. KUHN AND M. VELASCO
projection system. In J. F. DELAFRESNAYE (Ed.), Brain Mechanisms and Consciousne,'s, Blackwell, Oxford, and Masson, Paris, 1954, p. 81. 4 RosE, J. E., AND WOO~EY, C. N., A study of thalamo-cortical relations in the rabbit, Bull. Johns Hopkins Hosp., 73 (1943) 65-128. 5 RosE, J. E., AND WOOLSEY, C. N., Structure and relations of limbic cortex and anterior thalamic nuclei in rabbit and cat, J. comp. NeuroL, 89 (1948) 279-340. 6 ROSE, J. E., AND WOOLSEY, C. N., The orbitofrontal cortex and its cormections with the mediodorsal nucleus in rabbit, sheep and cat, Res. PubL Ass. nerv. ment. Dis., 27 (1948) 210-232. 7 SCHLAG, J., Reactions and interactions to stimulation of the motor cortex of the cat, J. Neurophysiol., in press. 8 Sa'~:FANIS, C., ANt> JASPER, H., Recurrent collateral inhibition in pyramidal tract neurons, J. Neurophysiol., 27 (1964) 855-877. 9 VEL~CO, M., AND LXNDSLEY,D. B., Role of orbital cortex in regulation of thalamocortical electrical activity, Science, 149 (1965) 1375-1377.
Brain Research, 2 (1966) 208-212