RECENT study has revealed a cephalically directed brain stem system whose stimulation desynchronizes the electrical activity of the cerebral cortex in a manner simulating that observed in awakening from sleep or in the EEG arousal reaction (8). This system was found to be distributed in the reticular formation of the medulla, the tegmentum of the pons and midbrain and the sub-and hypothalamus. The means by which its activating influence became exerted upon the cortex was speculated upon and, because of the generalized distribution of the cortical effects, it seemed likely that the diffuse thalamic projection system was concerned. Some evidence favoring this possibility was obtained but the problem was left for further investigation.Following preliminary determination of the organization of the diffuse thalamic projection system (12), the present study has explored this matter further: (i) by determining the thalamic regions whose electrical activity is desynchronized by stimulation of the reticular formation of the lower brain stem, (ii) by determining the distribution of thalarnic sites from which evoked potentials are recorded upon single shock stimuli to the reticular activating system, (iii) by exploring the thalamic areas whose direct excitation desynchronizes the electrocorticogram, (iv) by ascertaining the distribution of cortical potentials evoked by single shock stimulation of the reticular activating system, and (v) by determining the effect of diencephalic lesions on ascending conduction of the reticular influence. The results indicate that the ventromedial part of the thalamus is most critically involved in transmission of the reticular activating influence, with the rest of the thalamus (including the diffuse thalamic projection system) playing a subsidiary role. Evidence, moreover, is provided that a proportion of the influence of the reticular activating system upon the cortex may be exerted by an extra-thalamic route, paralleling that of the secondary response system described by Morison et al, (1, 10, 11). METHODSCats immobilized with B-erythroidine were used, with a Palmer respirator providing artificial respiration. Exposures were made under local procaine. S m d doses of chloralo---

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IN 1942, Dempsey and Morison (1-3, 9) discovered a thalamic system, low I frequency stimulation of which evoked widely distributed, high voltage, cortical waves, characterized by long latencies and initial progressive voltage i 1 increment. Attention was drawn to the close resemblance of these recruiting I , responses to spindle bursts, occurring spontaneously in barbiturate anesthesia, and evidence was presented that the two utilized common neural ' pathways. Since then, other proposals concerning the functional significance of this diffuse thalamic projection system have been made, the most dramatic being Jasper's hypothesis that it is the subcortical pacemaker in petit mal epilepsy (4,5,6). Recent demonstration that EEG activation by the brain stem may be mediated, in part at least, by the diffuse thalamic projection system (8, lo),has motivated the present attempt to learn more of its organization. The ' centre median and intralaminar nuclei were found by Dempsey and Morison .(9) to comprise the thalamic components of this system. In the absence of demonstrable connections from them to the cortex, their influence upon cortical electrical activity has since been proposed to be exerted indirectly,, .through the reticular thalamic nuclei (6, 11,12) or through the rhinenceph- METHODSCats were employed and the recruiting response, elicited by thalamic stimulation was ' recorded with a Grass model-3 amplifier and inkwriter. The animals were under nem-.butal, Dial or chloraloaane anesthesia or, after preparation under ether and local procaine, were immobilized with beta-erythroidine or by transection of the cord at C1 and maintained with artificial respiration. The thalamus was stimulated with stereotaxically oriented bipolar concentric electrodes. A Goodwin stimulator was employed, the condensor discharges of which had voltages between 1 and 7, a falling phase of 1 rnsec. and a usual frequency of ' 7.5/sec. Grounding both temporal muscles effectively reduced shock artifacts. Regional cortical pickups were between screw electrodes, 1 cm. apart, inserted into the calvarium until their tips rested on the underlying dura. More detailed pickup were obtained with silver ball tips, applied to the exposed cortex with the aid of a Graa~~ multiple electrode holder. The most precise cortical and subcortical records were gained with bipolar '

The convulsant drug, metrazol, has long been known to produce experimental seizures of the grand mal type and, more recently, has been employed clinically, either in shock therapy for patients with mental disease (11) or as an aid in the diagnosis of suspected epilepsy (2, 3, 8, 12, 16). Administration of subconvulsive doses of metrazol has been used to provoke abnormal discharge in the electroencephalogram of epileptic patients during inter-seizure periods (2, 12, 16). In addition similar doses of metrazol have been utilized in conjunction with photic stimulation (3) or direct stimulation of the brain (8) in the case of focal epilepsy, to induce controlled seizures. This usefulness of metrazol in the study of seizures in man makes it desirable to learn more of its action upon the brain (1, 4, 5, 9). The present experiments have investigated the alterations in cerebral electrical activity during metrazol seizures in the cat. Because of growing interest in subcortical influences upon the activity of the cerebral cortex, special attention has been directed to the participation of deep brain structures and, in particular, that of nuclei in the metrazol fit. METHODS Cats were prepared under ether, immobilized with B-erythroidine and maintained with a Palmer respirator. Metrazol was diluted in sterile water so that 1 cc contained 20 mg. and was administered intravenously. Electrical activity of the brain was recorded with an 8channel, Grass Model III amplifier and ink-writer, the emergency all-channel de-amplifier being used when seizure amplitude became excessive. Cortical electrodes consisted of the balled tips silver wires, oriented with the Grass multiple electrode holder. Deep electrodes were of the concentric bipolar type, oriented with a multiple electrode carrier and stereotaxic instrument; their placement being subsequently determined in microscopic sections. Click stimuli were delivered from a toy cricket, manually operated. Electrical stimuli to the brain consisted of condenser discharges with a falling phase of 1 m. sec. delivered from a Goodwin stimulator.

IN 1942, Dempsey and Morison (4-6, 24) discovered in cats a thalamic system which upon direct repetitive stimulation evoked recruiting wave responses in broad areas of the cortex. Evidence was presented that the physiological counterpart of this response to stimulation was burst or spindle activity recorded from the cortex of cats under surgical barbiturate anesthesia. Interest in the mechanism of the recruiting response has been heightened by proposals concerning its functional significance, the most discussed being Jasper's suggestion that it represents the basis for petit ma1 epilepsy (15,17,18).In the cat, sites of origin for the diffuse thalamic projection system have been found to be the centre median and intralaminar nuclei (24), as well as the ventralis anterior and rostra1 pole of the reticular nucleus (33). These component nuclei act as a functional unit for, on repetitive stimulation of any one of them, recruiting waves can be recorded froh all (33). The mediation of recruiting to the cortex has been suggested to occur either through the reticular nucleus throughout its extent (17, 30, 31) or by way of the rhinencephalon (31). It has been shown (33), however, that the principal transmission of recruitment to the cortex occurs through connections with the thalamic associational nuclei, although possibly some direct connections also exist between the recruiting nuclei of origin and the cortex. In accordance with these findings, the cortical responses were found to be limited to areas having projections from these association nuclei, with identical cortical localization irrespective of which recruiting nucleus was stimulated (33). The foregoing evidence in the cat suggested that the diffuse projection system is organized for mass thalamic influence on associational cortex (33). However, because of the relatively poor differentiation of the cat's associational nuclei and cortex, in the present study more conclusive evidence was sought in the macaque, which, with its higher order of both cortical and subcortical development, more closely simulates the human brain. METHODSAcute experiments were performed on 20 Macaca rnulatta monkeys, anesthetized with 30-35 mg./kg. Nembutal IV. Bipolar concentric electrodes, oriented with a Horsley-Clarke apparatus, were used to stimulate or pick up from the thalmus, using a polar distance between the tip and the barrel of 1 mm. or less. TO avoid the impaction of two electrode 1 Aided by a grant from the Commonwealth Fund. 2 Presented at the fall meeting of the A m e~c a n Physiolo@calSociety at Salt Lake City, September, 1951.