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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

[Changes in the electrical activity of the cerebral cortex under the combined influence of Cl. perfringens type A toxin and products of Cl. butyricum activity].

A study of the changes of the electrocorticogram (ECoG) and the electrocardiogram (ECG) in combined action of Cl. perfringens, type A, and of the Cl. butyricum broth culture filtrate showed that desynchronization of the cortical electrical activity and its subsequent depression occurred at earlier periods than in the case of isolated administration of Cl. perfringens toxin. The general character of the changes in the cortical rhythmic activity remained the same as in intoxication caused by Cl. butyricum toxin alone. The ECoG and ECG changes occurred at shorter intervals. Cl. butyricum filtrates induced no ECoG and ECG changes. It is supposed that the effect of the products of the Cl. butyricum vital activity consisted in increase in the tissue barrier permeability and, in this connection, in a greater penetration of Cl. perfringens toxin into the tissues, including the central nervous system.

Animals

Effect of arterial hypoxia on the cerebrocortical redox state, vascular volume, oxygen tension, electrical activity and potassium ion concentration.

The effect of different degrees of arterial hypoxia on cerebrocortical NAD/NADH redox state, reflectance, oxygen tension, extracellular potassium ion concentration, ECoG and arterial blood pressure was investigated in rats. The results may be summarized as follows. a) The decrease of cortical pO2 preceded the dilatation of cortical vessels by 15-20 sec but the changes in cortical extracellular potassium ion concentration, ECoG and arterial blood pressure started later than the vasodilatation. These results give further support to the regulatory role of cortical pO2 decrease in the initiation of cerebrocortical vasodilatation during arterial hypoxia. b) Since the K+ concentration of the brain cortex and the ECoG did not change in mild arterial hypoxia, the significant NAD reduction obtained in this experimental group is likely to be of cytoplasmic origin. The same conclusion applies to the initial periods of severe arterial hypoxia. On the basis of the extent of NAD reduction during various degrees of arterial hypoxia it is concluded that about 30% of the NAD reduction occurring in anoxia is of cytoplasmic origin. c) When the animals were ventilated with a gas mixture containing 4-7% oxygen, the brain cortex became nearly anoxic, partly because of the gradual decrease of arterial blood pressure. Finally, the mechanism of potassium leakage is identical under prolonged severe arterial hypoxaemia and on anoxic terminal depolarization.

Action Potentials

Stimulation of breathing movements in fetal sheep by inhibitors of prostaglandin synthesis.

We studied the effects of inhibitors of prostaglandin synthesis on fetal breathing movements on 17 occasions in 11 lambs (gestational age 125-141 days). We gave 12 h infusions of sodium mechlofenamate (8.6-22.2 mg.kg-1) in 13 studies and indomethacin (21.8-38.8 mg.kg-1) in four studies. Results were similar with both agents and did not correlate with drug dosage. There were no changes in fetal arterial blood pressure, pH or blood gas tensions. We assessed fetal breathing movements by measurements of tracheal pressure for a control period of 224 h prior to and 208 h during the infusion of inhibitors of prostaglandin synthesis; their administration caused a marked stimulation of fetal breathing movements judged from the following four variables: (1) incidence of fetal breathing movements increased from 38.4 to 69.2% of the time (P < 0.001); (2) average amplitude of change in tracheal pressure during fetal breathing movements increased from 4.1 to 6.0 torr (P < 0.01); (3) maximal amplitude of change in tracheal pressure during fetal breathing movements increased from 8.8 to 13.4 torr (P < 0.01); and (4) the duration of the longest continuous episode of fetal breathing movements increased from 37 to 229 min (P < 0.05). Two fetuses had electrocorticogram (ECoG) recordings. In control periods, fetal breathing movements occurred only during low voltage, high frequency ECoG activity; however, during infusions of inhibitors of prostaglandin synthesis, fetal breathing movements occurred also during high voltage, low frequency ECoG activity. We conclude that inhibitors of prostaglandin synthesis stimulate fetal breathing movement in fetal sheep. These results suggest that a component of the prostaglandin system is a factor which inhibits breathing movements during fetal life.

Animals

Desynchronization of electrical activity in rats induced by deprenyl--an inhibitor of monoamine oxidase B--and relationship with selective increase of dopamine and beta-phenylethylamine.

Electrophysiological and biochemical effects of deprenyl and beta-phenylethylamine were studied in rats. d,1-Deprenyl, 1-deprenyl (4-6 mg/kg) and beta-phenylethylamine (75 mg/kg) induced a desynchronization of ECOG after i.p. administration of drugs. The effects lasted several hours. The biochemical analysis indicate that d,1-deprenyl (4 mg/kg) nearly doubled the concentration of brain dopamine (DA) while the concentration of noradrenaline was not altered. The maximal increase was reached at 60 min and the enhanced concentration of DA stayed at this level up till 180 min after administration of drug. Treatment of rats with alpha-methyl-p-tyrosine (200 mg/kg) did not antagonize a deprenyl induced desynchronization of ECOG. However, even low dose of haloperidol (0.1 mg/kg) abolished the arousal effect of d,1-deprenyl and beta-phenylethylamine. It is suggested that desynchronization of EEG induced by deprenyl is more likely due to increased endogenous beta-phenylethylamine than to increased concentration of endogenous DA in the brain.

Acoustic Stimulation

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

Slow wave sleep and a state resembling absence epilepsy induced in the rat by gamma-hydroxybutyrate.

The effect of gamma-hydroxybutyrate (GHB) in relatively low doses (12.5--200 mg/kg) on sleep stages, electrocorticogram (ECoG) patterns and behavior was investigated in the rat. 50-100 mg/kg GHB induced slow wave sleep but, in contrast to the cat, not paradoxical sleep. 200 mg/kg induced a hypersynchronous, bilaterally symmetrical ECoG pattern, which was different in amplitude and frequency distribution from normally occurring high amplitude patterns. When the hypersynchrony occurred in bursts, the rats displayed a sudden arrest of motor behavior. Convulsions were not induced. The results, together with the finding of others that GHB is a natural constituent of mammalian brain and our previous observation that the GHB-induced hypersynchrony can be antagonized by anti-absence (anti-petit mal) drugs are discussed in view of the possibility that GHB might play a role in the etiology of absence epilepsy in man.

Animals

Suppression of an eplieptiform type of electrocortical activity in the rat by stimulation in the vicinity of locus coeruleus.

Stimulation of the locus coeruleus, or in the vicinity of this nucleus or of its ascending tracts, could markedly suppress the appearance of epileptiform-like ECoG bursts. The latter were induced in rats by a subconvulsive dose of pentylenetetrazol. Electrode sites were identified histologically. A unilateral stimulus suppressed bursts bilaterally. An individual burst already in progress could be aborted, stopping within less than 0.5-1 sec after onset of a stimulus train. The antiepileptiform actions occurred with no evidence of any desynchronizing effect of the stimulus on the resting ECoG; they appear to be different in sites of origin and nature from those reported for stimulation of the reticular activating system. It is proposed that stimulation of the ascending noradrenergic system in the brain stem may limit the development and spread of hyperexcitatory, epileptiform states.

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

Spectral density analysis of the effects of barbiturates and benzodiazepines on the electrocorticogram of the squirrel monkey.

The effects of pentobarbital and diazepam were compared in a series of tests in squirrel monkeys; the effects of phenobarbital and flurazepam were compared in a second series. Observations were made of gross behavior and on the ECoG; the latter was analyzed by the spectral density technique. The two barbiturates induced sedation,which was occasionally so deep that the monkeys could not be readily aroused. The benzodiazepines induced sedation in some monkeys, but others showed signs of restlessness. The ECoG showed general slowing with the barbiturates, whereas the benzodiazepines produced mixed fast and slow patterns. Spectral density analysis showed that pentobarbital increased activity at frequencies below 40 Hz, with the largest increases occurring below 8 Hz. Phenobarbital increased activity below 8 Hz, but differed from pentobarbital by decreasing activity above 13 Hz. The benzodiazepines increased activity below 8 Hz, decreased it between 8 and 20 Hz, and increased it between 20 and 50 Hz.

Animals

[Degree of homogeneity of the forms of statistical relationship between the EEG and spike currents of neurons].

The correlation between the spike activity and the waves of surface ECoG was studied in the visual and motor cortex of alert non-immobilized rabbits. A comparison was made between the forms of the obtained correlation functions for the cells with different horizontal and vertical distances between them. The analysis revealed the similarity of such functions in neurones of V-VI cortical layers, situated vertically under each other along the microelectrode track. Similar in form statistic connections between the ECoG and the background spike activity were also found, beginning with the depth of 1.000 mc, in the neurones situated at the same horizontal cortical level; however, with the increased distance between the cells the degree of similarity of these connections decreases in a non-linear way. On the basis of the obtained data a conclusion is made that the tangential sizes of the background functional ensembles of the cortical neurones are within the range of 140-300 mc.

Animals

Mechanism of the cerebrocortical vasodilatation during anoxia.

The possible role of cerebrocortical ion homeostasis, NAD/NADH redox state and of cortical oxygen tension was investigated in the initiation of hypoxic cortical vasodilatation. In addition, changes in cerebrocortical extracellular concentrations of Na+, K+, and Cl- during anoxia were studied. The results were as follows. a) The cerebrocortical reflectance decrease, e.g. cerebral vasodilatation, lagged behind the cortical pO2 decrease by 1-2 sec, but preceded the decrease of arterial blood pressure and ECoG as well as the extracellular Na+, K+, Cl- increases by 20-30 sec. Since the cortical pO2 decreased first and the ion changes lagged behind the onset of vasodilatation by 20-30 sec, it is suggested that the CBF increase in hypoxia is mediated via the cortical pO2 decrease. b) A significant NAD reduction was already present after 20 sec. of nitrogen breathing. Since the ECoG and MABP decreased, and K+ activity increased much later than this, it is presumed that the NAD reduction during the first 30-40 sec of anoxia indicates an increased rate of glycolysis, but not mitochondrial hypoxia. c) In the predepolarization phase a 17% K+, 4% Na+, 5% Cl- increase is probably the result of a reduction of the extracellular spaces caused by water movement and by the migration of Na+ and Cl- from the extracellular to the intracellular space. The large K+, Na+, Cl- changes during terminal depolarization can be interpreted as a result of the failure of the membrane bound Na+ -K+ pump and of the altered ion permeability of the cell membranes.

Action Potentials