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Modification of spontaneous ECoG and behavior in cat by monoamine precursors.

The effects of increasing the brain monoamine content on the three types of localized rhythms identified in somatic area I ("mu-type rhythms") were studied in freely moving cats. Increases in brain monoamines (catecholamines and serotonin) were produced by injecting L-Dopa and 5-HTP, L-tyrosine, L-tryptophan and tryptamine were also tested. It is concluded that the two subsets of rhythms, one accompanying high levels of alertness and vigilance and the other appearing during quiet wakefulness, are related to the catecholaminergic systems, while those characterizing drowsiness seem to be controlled by a serotoninergic system. The latter, however, is distinct from that controlling slow sleep.

5-Hydroxytryptophan

Suppression of cortical epileptiform activity by generalized and localized ECoG desynchronization.

The effects of high frequency electrical stimulation of both diffusely projecting brain regions and regions of more restricted projection were studied on penicillin-induced cortical epileptiform focal activity in the cat. Results obtained were contingent on the level of focal activity present at the time of stimulation. Very active foci (spike rates above 0.5/sec) were uniformly driven by stimulation of all structures under study. Foci exhibiting weak to moderate levels of activity were, on the other hand, inhibited both during and following stimulation. Episodes of spike suppression induced through stimulation of diffusely projecting structures were typically followed by an intensified "rebound" of interictal activity. Episodes of suppression induced through stimulation of regions of limited projection were not followed by such rebounds, an effect most dramatically apparent with caudate stimulation and motor cortex foci. Results are discussed in terms of the interaction between naturally occurring brain rhythms in sleep and arousal with the epileptic process.

Animals

Feasibility and efficacy of 5-azacytidine used early in the therapy of adult acute nonlymphocytic leukemia: an ECOG pilot study.

Ten of 19 adult patients (53%) with acute non-lymphocytic leukemia achieved a complete remission (CR) after receiving combination therapy with daunorubicin and cytosine arabinoside. The early administration of 5-azacytidine to treatment failures did not enhance the CR rate. Patients gaining CR received six monthly cycles of single-agent chemotherapy (5-azacytidine, daunorubicin, and cytosine arabinoside) sequentially as consolidation therapy over the next 7 months and no subsequent maintenance therapy. The median duration of CR is 10 months which is similar to previous studies. The early administration of 4-azacytidine did not increase the duration of remission, but was not associated with significant toxicity.

Adult

Restraint in primate chair may cause unusual behaviour in baboons; electrocorticographic correlates and corrective effects of diazepam.

Whereas primates restrained in a chair may usually be considered 'normal', the behaviour of baboons in this position was considerably altered: their eyes were closed and they only slightly reacted to the approach of the experimenter (opening of the eyes), in contrast with their active behaviour when left free to move about in their cage. When the ECoG was recorded from certain cortical areas (particularly somatic area I), an unusual pattern developed during the restrained state: 'drowsiness rhythms', which typically appear in this area during transition from wakefulness to sleep, developed in long sustained sequences. Administration of diazepam, an anxiolytic drug, caused both the behaviour and the ECoG of the restrained animal to return to normal (i.e., attentive behaviour and ECoG characteristic of the true waking state). The prolonged drowsy-like ECoG and behaviour may therefore underline a reaction to the 'stress' conditions brought on by restraint.

Animals

Local cerebral metabolism during enflurane anesthesia: identification of epileptogenic foci.

Electrocorticographic (ECoG) and depth recordings have previously demonstrated the epileptogenic nature of surgical concentrations of the volatile anesthetic enflurane. We contrasted ECoG activity with local cerebral glucose uptake [( 14C]2-deoxyglucose autoradiography) in 23 brain structures in order to identify the epileptogenic foci. Autoradiograms were obtained from sectioned rat brain following a 30 min period of steady-state anesthesia at 1, 1.5, or 2 MAC (minimum alveolar concentration) enflurane. Pseudo-epileptiform ECoGs were obtained at 1 MAC where bursts of slow waves and sharp waves were evoked by peripheral sensory stimulation. At 1.5 MAC, the ECoG displayed frank, spontaneous epileptiform activity with large amplitude spike-wave complexes; repetitive auditory stimulation occasionally precipitated grand-mal seizures. At 2 MAC, spike complexes were less frequent and could not be repetitively driven. At 1 MAC enflurane, regional cerebral metabolism was generally depressed approximately 14% from the awake controls. However, metabolism in the dentate gyrus of the hippocampus and other subcortical structures in the limbic brain was increased. At 1.5 MAC this dichotomy in local cerebral metabolic rate was maximal; we observed increased metabolism in the hippocampus, habenula, habenulo-interpeduncular tract and interpeduncular nucleus and pineal. Metabolism in all other structures was significantly depressed (P less than 0.05) compared to awake values. At 2 MAC, metabolism was decreased in all structures. We conclude that the low seizure threshold hippocampus and related structures associated with the limbic system and its pathways are the epileptogenic foci for seizures induced with enflurane in the rat. At 1.5 MAC, epileptiform activity spreads throughout the visceral brain when seizure threshold is at a minimum.

Anesthesia, General

[Evaluation by electrocorticogram of the protective action of piridoxilate against cerebral hypoxia in rats].

Piridoxilate, at the concentration of 120 mg/kg i.p. in rats, enhanced resistance of these animals to hypoxia (N2 : O2 3,2 %). The electrocorticogram (ECOG) is used to indicate the effectiveness of the drug in lowering the time of electrographic silence, on control (n=19) and pretreated rats (n=12). The ECOG was recorded also during the recovery period under pure oxygen. In pretreated rats, the ECOG records became flat in approximately 551 sec (versus 269 sec on the control group). The latent period of successive steps of cerebral anoxia were delayed in pretreated rats exposed to hypoxia. During the recovery period, piridoxilate seems to enhance the restoration of normal ECOG, as a function of the duration of hypoxia.

Animals

The effects of a spirolactone derivative on EEG and cortical single unit activity in the cat.

With systemic (60-150 mg/kg) and topical application, Aldactone exhibited strong convulsant action on the cat cerebral cortex. The most common abnormal interictal features of the surface ECoG pattern were sequences of fast waves and slow negative waves associated with positive sharp waves, negative field potentials and burst-like neuronal activation in the extracellular microelectrode record. Another abnormal pattern was a period of ECoG and neuronal inactivity subsequent to the negative transients. These series of sharp and slow waves and of inactivity were interrupted by tonic and clonic ECoG seizures characterized by regular surface positive spikes. Development of seizures, but not of interictal phenomena, could be prevented by intravenous application of Diazepam (1 mg), Nembutal (30 mg/kg) and--less effectively--by Phenhydane (20 mg/kg).

Administration, Topical

Differential arousal response to gustatory stimuli in the awake rabbit.

ECoG arousal response as elicited by deionized water and by several concentrations of sweet, salty, sour and bitter tasting substances, all applied intraorally, were studied in the awake restrained rabbit. The study was carried out on 17 chronic preparations of adult male animals (2.6 kg average body weight). Water as a stimulant was presented in 60 trials and tastants across qualities and concentrations in 245 trials. Arousal was quantitatively characterized by its duration, frequency increment and amplitude decrement as compared to prestimulus conditions. Arousal induced by tastants was compared to that induced by water. Water and tastants induced arousals differentiable by the parameters measured. Further, most tastants produced a dose-dependent response. Comparison of ECoG and behavioral data clearly indicate that tastants inducing behavioral aversion also produce an arousal which significantly differs from response to water while behavioral preference was found not to show similar correspondence with ECoG data. The possibility of using arousal as an objective indicator for taste aversion is discussed.

Acetates

Overall survival of immunotherapy versus standard of care in chemorefractory microsatellite stable metastatic colorectal cancer: a propensity score matched analysis of 708 patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC). However, selected patients with specific metastatic patterns may derive benefit. METHODS: Patients with chemorefractory pMMR/MSS mCRC treated with ICI-based regimens were retrospectively identified. A comparison cohort treated with trifluridine/tipiracil&#xb1;bevacizumab, regorafenib, or fruquintinib as standard of care (SOC) was generated through 1:1 propensity score matching by age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), liver metastases (present/absent), and RAS/BRAF status. Overall survival (OS) was compared using Cox regression. RESULTS: A total of 354 patients treated with ICIs and 354 treated with SOC were matched. Median age was 55 years, 52% male, 32% ECOG PS 0, 30% right-sided, and 69% RAS mutated in both groups, while 61% and 60% had liver metastases, respectively. Median OS (mOS) was 10.8 months with ICIs and 9.0 months with SOC (HR 0.76, 95%&#x2009;CI 0.64 to 0.92, p=0.004). In patients without liver metastases, mOS was longer with ICIs than SOC (19.1 vs 13.2 months, HR 0.59, 95%&#x2009;CI 0.43 to 0.80, p<0.001), whereas outcomes were similar in patients with liver metastases (6.4 vs 6.5 months, p=0.303). In univariable analyses, age, sex, primary tumor site, and RAS/BRAF status were not associated with OS. Treatment with ICIs, absence of liver metastases, one prior line of therapy, less than three metastatic sites, and ECOG PS 0 were associated with the most favorable outcomes in univariable and multivariable models. CONCLUSIONS: In chemorefractory pMMR/MSS mCRC without liver metastases, ICI-based regimens yielded longer OS than SOC. Further investigation of ICIs in this patient population is warranted.

Humans

Brain energy metabolism of the conscious rat exposed to various physiological and pathological situations.

Using a time-sharing fluorometer-reflectometer, pyridine nucleotide (NADH) and flavoprotein (Fp) fluorescence, as well as reflected light at the excitation wavelength, were measured and correlated with the electrical activity of an awake cerebral cortex. Exposure of the rat to a nitrogen atmosphere (anoxia) led to an increase in signals representing the reduction of pyridine nucleotides and flavins, with very similar kinetics. Inducement of partial ischemia by bilateral carotid artery ligation led to an increase in NADH, accompanied by a very small effect on the electrical activity (ECoG). In most animals, 2-3h after ligation, the ECoG became flat or depressed. Exposure of this ischemic cerebral cortex to KC1 solution caused depression of the electrical activity without metabolic response probably due to the limitation of oxygen supply. The metabolic state of an awake cerebral cortex was identified by exposing the brain to various levels of oxygen, epileptoform activity, spreading depression, hyperbaric pressure of oxygen and an uncoupler. From our results we conclude that the awake cerebral cortex is close to the resting state, state 4, rather than to the active state, state 3.

Animals

The effects of local micro injections of opiates and enkephalins into the forebrain on the electrocorticogram of the rat.

The effects of various opiate compounds have been studied on the electrocorticogram (ECoG) of the rat following local injection into various brain areas. Injections of all compounds studied into both the caudate-putamen and the basal forebrain, in particular the olfactory tubercles, induced changes in the ECoG. Injections of saline vehicle into these areas were ineffective as were injections of morphine into the corpus callosum. Potency was etorphine greater than morphine = codeine greater than thebaine. Naloxone alone was inactive following injection but if combined with morphine markedly attenuated the normal morphine response and reversed the morphine response if injected following morphine. The endogenous opiate compound enkephalin and the synthetic analogue D-ala2-met5-encamide also induced electrocortical changes which were naloxone sensitive. The results are similar to those following systemic administration of opiates. It is possible that the areas studied represent the site of action of systemically applied opiates. It is suggested that the opiates and enkephalins produce their actions by acting at the same site. Since the areas studied are rich in dopaminergic terminals an interaction may exist between dopaminergic and opiate mechanism to bring about the observed changes.

Animals

A clinically effective spike recognition program: its use at electrocorticography.

This automated system detects spikes when the first derivative value of the EEG or ECoG signal exceeds a user-determined threshold twice, with reversal of direction, within 30--80 msec. The EEGer selects this threshold by his assessment of the system's initial performance in a recording situation. By combining the spike detecting abilities of both the EEGer and computer, two tasks can be accomplished on-line for 16-channel EEG or ECoG: (1) localization of the origin of widely synchronous spikes, and (2) assessment of the relative quantities of spikes emanating from several active regions. This system achieved a human-computer correlation ranging from 0.79 to 0.84.

Action Potentials

Myoclonus developing after vermisectomy in photosensitive Papio papio.

Two vermisectomized photosensitive baboons exhibited two different types of myoclonus, one induced by intermittent light stimulation (ILS) and the other occuring "spontaneously". The characteristics of these two types of myoclonus are described from a clinical and from an ECoG point of view. Myoclonus induced by ILS (ML) started at the eyelids and secondarily invaded the face and body; it was always preceded by frontorolandic spike-waves or polyspike-waves. The "spontaneous" myoclonus which followed vermisectomy (MV) was "massive", but involved firstly the trunk and secondarily the face and limbs; no ECoG paraoxysm accompanied this myoclonus, but we observed a parietal evoked potential of small amplitude, 10--15 msec after its onset. If MLs can be considered as consequences of the fronto-rolandic paroxysmal discharges, MVs seem to originate in the brain stem but appear similar to action myoclonus. This experimental situation showing two types of myoclonus resembles human hereditary degenerative syndromes (dyssynergic cerebellar myoclonus, progressive myoclonic epilepsy), without being exactly comparable. The conditions in which MVs were seen and their modifications during sleep and by different drugs are described. The relationships between MVs and MLs and myoclonic epilepsy are discussed.

Animals

Coupling between neuronal activity and focal blood flow in experimental seizures.

Local blood flow, ECoG and single cortical neurone activity were recorded simultaneously from single microelectrodes in 17 cats. Seizures were induced by repeated intravenous injections of pentylenetetrazol (PTZ, 10-20 mg/kg) or by local application of 1 M Na-penicillin. Seven to 20 sec after appearance of burst activity in cortical neurones and ECoG, focal flow increased up to 300% of control. The extent of this flow increase was significantly correlated with the change in firing rate of the neurones. With cessation of seizure activity the flow returned to or below control values. Forty to 70 mg/kg PTZ caused status epilepticus with high voltage rhythmic discharges lasting 30 min-2 h. In 3 cats with status, the flow decreased below control despite persisting seizures, indicative of uncoupling between activity and flow. The delayed coupling between activity and flow during drug-induced seizures indicates a metabolic mediator. Uncoupling observed in cases with long lasting seizures may be due to brain oedema following increased permeability of the blood-brain barrier.

Animals

The role of dopaminergic systems in gamma-hydroxybutyrate-induced electrocorticogram hypersynchronization in the rat.

The effects of dopaminergic agonists and antagonists on the duration of hypersynchronization induced in the electrocorticogram (ecog) by gamma-hydroxybutyrate (gamma-HB) were tested in rats. Apomorphine (0-2-8 mg kg-1), piribedil (2-5-10 mg kt-1) and haloperidol (0-5-1 mg kg-1) had no influence on the duration of the hypersynchrony. Amphetamine (1-5-6 mg kg-1) inhibited the hypersynchrony, while (3,4-dihydroxyphenylamino)-2-imidazoline (DPI; 5, but not 1, mg kg-1) prolonged its duration. The lack of effect of the dopamine receptor agonists apomorphine and piribedil, and the dopamine receptor blocker haloperidol, on the gamma-HB-induced hypersynchrony might indicate that the inhibition of the impulse flow in the nigrostriatal dopamine system by gamma-HB is not involved in the generation of the hypersynchrony. DPI is thought to be an agonist at a dopamine receptor not sensitive to apomorphine, and its facilitatory effect on gamam-HB-hypersynchrony can be interpreted in terms of a possible involvement of another dopamine system in the ecog hypersynchrony induced by gamma-HB. The antagonism of gamma-HB by amphetamine is possibly due to an indirect stimulatory effect on noradrenergic receptors.

Amphetamine