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Lack of interhemispheric transfer of the 1-Hz suppression effect in rats
Abstract
Three experiments were conducted to evaluate the effect of 1-Hz brain stimulation of the amygdala on kindling behavior induced by 60-Hz sine-wave stimulation in the contralateral amygdala. In Experiment 1, the effective threshold intensity (ETI) to elicit a kindled response with 60-Hz stimulation was determined on four separate occasions with 15 trials between determinations (three per day) for each of three groups. Experimental rats in Group 1 were stimulated with 1-Hz sine waves in one amygdala, then with 60-Hz current in the opposite amygdala, followed by 1-Hz stimulation of the first site (1-60-1, OA), with 1-h interstimulation intervals. Group 2 was treated with the 1-60-1 pattern, but with all stimulation in the same amygdala (1-60-1, SA). Group 3 received only the 60-Hz stimulation trials (X-60-X), on the second trial. Group 2 showed the typical suppression result, a gradual increase in threshold over the four ETI determinations. However, Group 1’s responses were similar to those of Group 3: ETI values decreased gradually over the determinations. Later, when Group 1 received a set of trials in which 1- and 60-Hz current stimulation was to the same site, suppression responses occurred. Two further experiments were conducted with similar results. These results suggest that the suppression effect generated by 1-Hz stimulation appears to involve a local process, an intrahemispheric effect.
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: The kindling phenomenon is a progressive increase in the strength of epileptiform activity evoked by spaced (in time) and repeated electrical stimulation of certain brain structures. The work that has been done on the kindling phenomenon is reviewed, with an emphasis on those studies that deal with underlying mechanisms. Based on the work that has been done thus far, it is clear that the kindling effect is not due to any type of gross tissue damage. It is also clear that at least some of the effects are due to changes at the synapse and that these changes are widely distributed in the brain. The changes might be due to an increasing efficacy at excitatory synapses or a decreased effectiveness at inhibitory synapses, or both. The long term post-tetanic potentiation data and some preliminary electron microscopic studies support the former mechanism, whereas the depletions of catecholamines in kindled tissue support the latter. In addition to these transynaptic changes, there may be other changes that occur at the site of the stimulating electrode, and these changes may be based on a different mechanism. These ideas and the relevant data are discussed. Copyright (C) by the Congress of Neurological Surgeons
Experiments were conducted to evaluate the effect of various durations of 3-Hz brain stimulation on kindling behavior induced by 60-Hz sine-wave stimulation of the amygdala. In two experiments the effective threshold intensity (ETI) to elicit a convulsion was determined on four separate occasions with 5 days of daily trials interspersed between determinations. On each day experimental rats were stimulated with 3-Hz current on the first and third trials for 5, 15, 30, 60, 120, or 300 sec duration and with 60-Hz current for 30 sec on the second trial. A steady increase in the intensity required to elicit a convulsion with 60-Hz current from ETI1 to ETI4 resulted for all rats with durations of 15 sec or greater. Rats stimulated only with 60-Hz sine waves and those in the 5-sec group maintained relatively stable values from ETI1 to ETI4, with a slight decline occurring. Suppression of the expected 60-Hz-induced convulsive behavior on daily trials was modest in the 15-sec group, pronounced with the 30-sec group, and drastic with the other groups. The 300-sec group had the greatest suppressive effect operating. The suppression effect appeared not to be due to tissues damage inasmuch as many of the experimental rats (except the 300-sec group) convulsed again at previous low ETI levels following a 16-day rest at the end of the experiment. This result suggests that the suppression effect is a relatively transient event.
These exploratory experiments investigated the effect of 3-Hz brain stimulation on behavior induced by 60-Hz brain stimulation when the former was presented simultaneously with, or following, the latter. In the simultaneous case, 3-Hz stimulation to one amygdala and 60 Hz to the other produced a slower kindling rate than did bilateral stimulation with 60 Hz. When 3-Hz stimulation followed six convulsion trials of 60-Hz stimulation, there was no effect on the convulsive tendency; however, with rats in which the convulsive pattern was relatively stable and 48 or more convulsive trials were followed by 24 trials of 3-Hz stimulation at double intensity or 36 trials at the same intensity as previous 60-Hz stimulation, a reversal effect was observed, that is, a return to nonconvulsive behavior.
There are three types of interference effects during kindling: that produced by alternate stimulation of homologous brain sites, by successive stimulation of one site, and by stimulation of one site by different frequencies. These three types of interference appear to be similar. Facilitation and interference effects during kindling seem to be generated by the operation of two factors: a “neurological trace” process, possibly involving synaptic changes, and an “aftereffect.” The latter process may be the main basis for these interference effects.
Rats with multiple recording and stimulating electrodes were stimulated electrically in the amygdala, hippocampus and reticular formation. Intensity of stimulation was varied in a systematic way to determine the threshold at which after-discharges (ADs) were produced in the vicinity of the stimulating electrode. AD thresholds were permanently reduced by 40–60% in the amygdala and 25% in the hippocampus by daily 1 sec bursts of stimulation. The reduction took place with subthreshold as well as suprathreshold stimulation, but not in the absence of stimulation.It was found that the reduction of AD thresholds in the amygdala had no effect on AD thresholds in the contralateral amygdala, septal area or hippocampus. Reduction of AD thresholds in the hippocampus, however, resulted in an increase in the AD threshold in the contralateral hippocampus.RésuméDes rats porteurs d'électrodes de stimulation et d'enregistrement multiples ont subi une stimulation électrique de l'amygdale, de l'hippocampe et de la formation réticulaire. L'intensité de la stimulation varie de façon systématique afin de déterminer le seuil auquel les post-décharges sont produites dans le voisinage de l'électrode de stimulation. Les seuils de post-décharge sont en permanence abaissés de 40 à 60% dans l'amygdale et de 25% dans l'hippocampe par des bouffées quotidiennes de stimulation durant une seconde. Cet abaissement survient aussi bien pour des stimulations sous-liminaires que sus-liminaires, mais non en l'absence de stimulation.L'auteur observe que la réduction des seuils de post-décharges dans l'amygdale n'a aucum effet sur les seuils de post-décharge dans l'amygdale controlatérale, la région septale ou l'hippocampe. L'abaissement des seuils de post-décharges dans l'hippocampe, par contre, provoque une augmentation du seuil de post-décharge dans l'hippocampe controlatéral.
The kindling phenomenon is a progressive increase in the strength of epileptiform activity evoked by spaced (in time) and repeated electrical stimulation of certain brain structures. The work that has been done on the kindling phenomenon is reviewed, with an emphasis on those studies that deal with underlying mechanisms. Based on the work that has been done thus far, it is clear that the kindling effect is not due to any type of gross tissue damage. It is also clear that at least some of the effects are due to changes at the synapse and that these changes are widely distributed in the brain. The changes might be due to an increasing efficacy at excitatory synapses or a decreased effectiveness at inhibitory synapses, or both. The long term post-tetanic potentiation data and some preliminary electron microscopic studies support the former mechanism, whereas the depletions of catecholamines in kindled tissue support the latter. In addition to these transynaptic changes, there may be other changes that occur at the site of the stimulating electrode, and these changes may be based on a different mechanism. These ideas and the relevant data are discussed.
The kindling effect is described as involving a gradual change in behavior in response to periodic invariant electrical stimulation of specific brain sites, culminating in convulsions. Two premises are evaluated relative to kindling: (a) The kindling effect provides an excellent model of human epileptic conditions. (b) The amino acid taurine will act to suppress convulsions developed during kindling. Consideration of behavioral, electrophysiological, neurological, and chemical aspects of kindling suggest that behavioral aspects may model those of epilepsy, but it is probable that neurological mechanisms in some types of epilepsy are different from those underlying the kindling event. Although taurine appears to have an important role (e.g., as an inhibitory neurotransmitter) and has been successful in suppressing convulsions in humans and in some experimentally induced seizures, it has been found to have no effect on convulsions developed via kindling. (65 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Rats were kindled until each periodic, bipolar, amygdaloid stimulation reliably elicited and afterdischarge and a generalized motor seizure. The inhibitory effects of one amygdaloid stimulation (antecedent stimulation) on the afterdischarges and motor seizures typically produced by the next (test stimulation) were studied in a series of experiments. Levels of antecedent stimulation which themselves elicited afterdischarges and motor seizures produced marked inhibitory effects which dissipated in approximately 90 min, whereas levels of antecedent stimulation which elicited local afterdischarges but no motor seizures had only mild inhibitory consequences. Regardless of their intensity, stimulations which evoked no epileptic responses themselves did not inhibit the responses to subsequent test stimulations. The inhibitory effect of a series of antecedent stimulations was more complex than that produced by a single stimulation. A series of 19 kindled motor seizures was elicited by amygdaloid stimulations applied at 1.5-h intervals without any indication of inhibitory effects; however, the next day the response to a single amygdaloid stimulation was almost completely suppressed. This marked inhibitory effect dissipated gradually during the next 5 days.
Daily unilateral electrical stimulation of amygdala in forebrain bisected cats provoked the development of the final stage of the kindled convulsion with remarkable rapidity regardless of presence or absence of anterior commissure. The chronological and spatial pattern of propagation of afterdischarge, interictal spike discharge, and clinical manifestations strongly suggest the significant role played by the midbrain reticular formation and possibly other brainstem structures in the progressive electroclinical seizure development. This assumption was supported by the results of a lesion study in which placement of a destructive lesion in the ipsilateral midbrain reticular formation markedly increased the generalized seizure triggering threshold, lateralized the afterdischarge to the stimulated hemisphere when induced with increased intensity stimulation, fragmented clinical seizure manifestations, and failed to produce progression of clinical and electrographic events with prolonged daily stimulation. This is in contrast to the insignificant effect produced by a peduncular lesion. Our findings suggest that vertical (limbic-brainstem), but not horizontal (transhemispheric interlimbic) connection is critically involved in the amygdaloid seizure development while the forebrain commissures may play a role in the development of bisynchronous and bisymmetrical ictal and interictal electrographic and clinical manifestations. Finally, possible differential effect of forebrain bisection depending on developing in contrast with a established (cerebral) hemispheric epileptogenic process is postulated to explain the "facilitatory" effect observed in our series in contrast to the beneficial effects reported on some intractable seizure patients.
Bipolar electrodes were implanted into the amygdala of each hemisphere of adult male rats. A short burst of low-intensity stimulation was applied to one of these electrodes once each day. Initially there was little response. With repetition, epileptiform responses progressively developed until each daily stimulus triggered a behavioral convulsion (kindling effect). Following six convulsions, the procedure was applied to the contralateral hemisphere. Convulsions were observed to kindle more rapidly, especially if a rest interval of 2 weeks followed the last primary site convulsion. When stimulation was reapplied to the primary site, convulsions were not triggered. This was associated with failure to evoke local after-discharge and/or failure of the after-discharge to propagate. Several trials were necessary to re-establish convulsion, unless a 2 week rest preceded testing, in which case convulsions were triggered on the first trial. Following a series of convulsions triggered from either hemisphere, the contralaterally triggered convulsions, when they appeared, showed consistently longer onset lattencies. These latency shifts were attentuated when rest intervals preceded the testing. Latency shifts and seizures failures were not observed if the preceeding series of convulsions was reduced from six to one. Lesions at the tip of either electrode had little effect on the results obtained in the contralateral hemisphere. Together, the results imply that: kindling establishes a lasting trace which is both transynaptic and widespread, kindling from a second location establishes a second trace utilizing parts of the existing trace, a series of convulsions leaves a less durable after-effect with a decay time of about 2 weeks and which interferes with various aspects of seizure activity, and the trace which activates the convulsions is less susceptible to interference from the after-effect.
Brief bursts of nonpolarizing electrical brain stimulation were presented once each day at constant intensity. At first the stimulation had little effect on behavior and did not cause electrographic afterdischarge. With repetition the response to stimulation progressively changed to include localized seizure discharge, behavioral automatisms and, eventually, bilateral clonic convulsions. Thereafter, the animal responded to each daily burst of stimulation with a complete convulsion. The effect was obtained from bipolar stimulation of loci associated with the limbic system, but not from stimulation of many other regions of the brain. Parametric studies and control observations revealed that the effect was due to electrical activation and not to tissue damage, poison, edema, or gliosis. The changes in brain function were shown to be both permanent and trans-synaptic in nature. Massed-trial stimulation, with short inter-burst intervals, rarely led to convulsions. The number of stimulation trials necessary to elicit the first convulsion decreased as the interval between trials approached 24 hours. Further increase in the inter-trial interval had little effect on the number of trials to first convulsion. High-intensity stimulation studies revealed that the development of convulsions was not based simply on threshold reduction, but involved complex reorganization of function. Experiments with two electrodes in separate parts of the limbic system revealed that previously established convulsions could facilitate the establishment of a second convulsive focus, but that the establishment of this second convulsive focus partially suppressed the otherwise permanent convulsive properties of the original focus.
An experiment was conducted to evaluate the effect of various frequencies of brain stimulation on kindling behavior induced by 60-Hz sine wave stimulation. The effective threshold intensity (ETI) to elicit a convulsion was determined on four separate occasions with 5 days of daily trials between determinations. On each day experimental rats were stimulated with current of a specific frequency on the first and third trials for 60 seconds duration and with 60-Hz current for 30 seconds on the second trial (one hour intertrial interval). There were five experimental groups, one each for 1, 5, 10, 30, and 60-Hz stimulation. A sixth group received no stimulation on trials 1 and 3 and 60-Hz current on trial 2. Suppressor of convulsive behavior induced by the 60-Hz stimulation trial was present for all ETI determinations with 1-Hz and 5-Hz stimulation; the mean ETI increased on each successive determination. Suppression was prominent also for the 10-Hz group until the ETI4 determination. Suppression was moderate for the 30-Hz and 60-Hz groups. Overall, it appeared that the interference effect gradually increased with remoteness from the 60-Hz point.
Experiments were conducted to evaluate the effect of two intertrial intervals of 1-Hz brain stimulation on kindling behavior induced by 60Hz sine wave stimulation. In two experiments, the effective threshold intensity (ETI) to elicit a convulsion was determined on four separate occasions with 5 days of daily trials between determinations. On each day experimental rats were stimulated with 1-Hz current on the first and third trials for 120 seconds duration and with 60-Hz current for 30 seconds on the second trial (1-60-1 group). A second group was stimulated with 60-Hz-current on each trial (60-60-60 group). A third group received no stimulation on Trials 1 and 3 and 60-Hz current on Trial 2 (X-60-X group). In Experiment 1, the intertrial interval was 3 hours; a 24 hour interval was used in Experiment 2. The results were similar in both experiments. For the 1-60-1 group, there was a steady increase in the intensity required to elicit a convulsion shown with 60-Hz current from EtI1 to ETI4. However, the 24 hour interval produced a lesser effect than did 3 hour interval (or the 1 hour interval used in previous experiments). Rats in the other groups maintained relatively stable values from ETI1 to ETI1, with a slight decline occurring. Suppression of convulsive behaviour on daily trials was present with the 1-60-1 groups, and nonexistent with the other groups.
An experiment was conducted to evaluate the effect of 1-Hz or direct current brain stimulation on kindling behavior induced by 60-Hz sine wave stimulation. The effective threshold intensity to elicit a convulsion was determined on four separate occasions with 5 days of daily trials between determinations. On each day one group of experimental rats was stimulated with 1-Hz sine wave current before and after stimulation with 60-Hz sine wave current (1-60-1 group). Another group received direct current stimulation and 60-Hz current (D-60-D group). A third group received only 60-Hz stimulation. Suppression of kindling behaviour usually induced by the 60-Hz stimulation occurred with 1-Hz stimulation; the mean threshold value increased on each successive determination. Suppression was most pronounced for the direct current group; it appeared after a single trial and persisted for 32 days after the last threshold determination. In contrast, most of the rats in the 1-60-1 group had recovered from the suppression after the 32 day period of nonstimulation. A second phase of the experiment indicated that the increase in threshold values for the D-60-D group occurred after a single DC stimulation. These results are consistent with the hypothesis generated by previous research that suppression following 1-Hz stimulation is not due to tissue damage.
Experiments were conducted to evaluate the effect of 3 Hz brain stimulation on kindling behavior induced by 60 Hz sine waves stimulation. In Experiment 1,12 rats were subjected to 40 or 60 convulsion trials with 60 Hz stimulation and then given 36 trials of 3 Hz stimulation. Whe'n these rats were stimulated again with 60 Hz sine wave current at the same brain site, none of the rats showed a convulsion in nine test trials. The intensity of stimulation had to be increased on test trial 10 to elicit convulsions for each rat. Of 10 rats in two control groups, only 1 did not convulse during the nine test trials. In Experiment 2 the effective threshold intensity (ETI) to elicit a convulsion was determined on five separate occasions with 10 days of daily trials between determinations. On each day experimental rats were stimulated with 3 Hz current on the first and third trials and with 60 Hz current on the second trial (3–60‐3 group). A steady increase in the intensity required to elicit a convulsion with 60 Hz current from ETI, to ETI 5 resulted. Rats stimulated only with 60 Hz sine waves on the second trial each day (X‐60‐X group) maintained relatively stable values from ETI, to ETI 5 . In the four, 10‐day blocks of trials, convulsions were suppressed in 20% to 80% of the trials over the 10 day period for the 3–60‐3 group, with the greatest effect occurring after about 4 days of stimulation. This suppressive effect was prominent both with rats that were at the convulsion stage prior to the first application of 3 Hz stimulation and with rats that were at preconvulsion stages. In Experiment 3 the permanency of the suppressive effect was evaluated. Eight suppressed rats from the experimental group in Experiment 2 and 4 control rats were stimulated for 90 trials over 30 days with 60 Hz current, and ETI values were determined after each set of six trials. Four of the 8 experimental rats were convulsing at ETI,. within 20 days.
RÉSUMÉ
Des expériences ont été réalises afin d'évaluer les effets d'une stimulation cArébrale à 3 Hz sur l'effet d'embrasement obtenu par une stimulation sinusoïdale à 60 Hz. Dans la première série expérimentale, 12 rats ont été stimulés 40 à 60 fois avec une fréquence de 60 Hz capable d'induire des convulsions, puis 36 fois avec une fréquence de 3 Hz. Lorsque ces rats ont étéà nouveau stimulés, au niveau de la même structure cérébrale, avec un courant sinusoïdal à 60 Hz, aucun d'eux n'a présenté de convulsions au cours des 9 stimulations tests suivantes. l'intensité de la stimulation a dûêtre augmentée au cours de la dixième stimulation test pour que survienne une convulsion chez chacun des rats. Parmi les 10 rats de deux groupes de contrôle, un seul d'entre eux n'a pas convulsé pendant les 9 stimulations tests. Dans la deuxième série expérimentale, l'intensité seuil efficace (ISE) pour induire une convulsion a étéévaluée de façon précise à cinq occasions différentes. Ces évaluations précises ont été effectuées a 10 jours d'interfalle pendant des périodes où l'animal était stimulé tous les jours. Chaque jour les rats d'expériences étaient stimulés avec un courant à 3 Hz la première et la troisième fois et avec un courant à 60 Hz la seconde fois (groupe 3–60‐3). II en est résulté une augmentation stable de l'intensité du courant à 60 Hz nécessaire pour induire une convulsion en allant de ISE, à ISE 5 . Les rats qui ont été seulement stimulés chaque jour avec un courant sinusoïdal à 60 Hz ont gardé, lors de laseconde stimulation (groupe 3‐60‐3), des valeurs relativement stables en allant de ISE, à ISE,. Dans les quatre séries de 10 jours, au cours desquelles l'animal était stimulé journellement, les convulsions étaient supprimées entre 20 et 80% des fois, lorsqu'il était stimulé selon le protocole du groupe 3–60‐3 pendant 10 jours; l'effet le plus important s'est fait sentir après environ 4 jours de stimulation. Cet effet suppressif était plus important aussi bien chez les rats qui avaient atteint le stade de la convulsion avant l'application de la première stimulation à 3 Hz que chez ceux qui n'étaient encore qu'au stade préconvulsif, lorsque celle‐ci a commencéàêtre appliquée. Dans la troisième série expérimentale, la durée de cet effet suppressif a étéévaluée. 8 rats de la série expérimentale 2, chez lesquels les convulsions avaient été supprimées, et 4 rats contrôles ont été stimulés avec un courant à 60 Hz 90 fois pendant 30 jours; les valeurs d'ISE ont étéétablies de façon précise après chaque série de 6 stimulations. 4 des 8 rats expérimentaux ont convulsé dans les 20 jours au cours de ISE 1
RESUMEN
Se han realizado experimentos para valorar el efecto de la estimulación cerebral (3‐Hz)sobre el comportamiento inducido (Kindling) con estimulación cerebral de onda sinusal de 60‐Hz. En el Experimento I, 12 ratas fueron sometidas a 40 o 60 ensayos convulsivos con estimulación de 60‐Hz y, posteriormente, se añadieron 36 ensayos con estimulación de 3‐Hz. Cuando estas ratas fueron estimuladas nuevamente con corriente de ondas sinusales de 60‐Hz en el mismo lugar cerebral, ninguna mostró convulsiones en nueve ensayos. Fue necesario un aumento de la intensidad de la estimulación en el ensayo 10 para detectar una convulsitin en cada rata. Solamente una rata no convulsionó de 10 ratas en dos grupos control durante nueve ensayos. En el Experimento 2 el umbral de la intensidad efectiva (ETI) para producir una convulsión se determineó en cinco ocasiones distintas durante 10 dias de ensayos diarios entre las determinaciones. Las ratas fueron estimuladas diariamente con corriente de 3‐Hz en el primer y tercer ensayo y con corriente de 60‐Hz en el segundo ensayo (grupo 3–60‐3). En estas condiciones se necesitó un aumento continuo en la intensidad requerida para producir una convulsión con corriente de 60‐Hz desde ETI 1 a ETI 5 Las ratas que solo se estimularon con ondas sinusales de 60‐Hz en el segundo ensayo de cada dia (grupo X‐60‐X) mantuvieron unos niveles relativamente estables desde ETI 1 , a ETI 5 . En los cuatro bloques de diez dias de ensayos se consiguió una supresión de las convulsiones en un 20 a un 80% de los ensayos durante el periodo de diez dias para el grupo 3–60‐3 con el mayor efecto a partir del cuarto dia de estimulación. Este efecto supresor fue prominente en las ratas que estaban en estado con‐vulsivo previo a la primera aplicación de la estimulación de 3Hz y tambien en las ratas que permanecian en periodos preconvulsivos. En el Experimento 3 sevaloró la persistencia del efecto supresor. Ocho ratas suprimidas pertenecientes al grupo experimental en el Experimento 2 y cuatro ratas control fueron estimuladas para 90 ensayos durante más de 30 dias con corriente de 60‐Hz determineándose los valores de ETI tras cada grupo de 6 ensayos. Cuatro de las ratas experimentales convulsionaron a ETI 1 , en un plazo de 20 dias.
Experiments were conducted to evaluate the effect of various durations of 1-Hz brain stimulation on kindling behaviour induced by 60-Hz sine wave stimulation. In two experiments the effective threshold intensity (ETI) to elicit a convulsion was determined on four separate occasions with 5 days of daily trials interspersed between determinations. On each day experimental rats were stimulated with 1-Hz current on the first and third trials for 5, 15, 30, 60, 120, 180, or 600 seconds duration and with 60-Hz current for 30 seconds on the second trial. A steady increase in the intensity required to elicit a convulsion with 60-Hz current from ETI2 to ETI4 resulted for all rats with durations of 15 seconds or greater. Rats stimulated only with 60-Hz sine waves, and those in the 5 second group, maintained relatively stable values from ETI1 to ET4, with a slight decline occurring. Suppression of convulsive behavior on daily trials was modest in the 15 second group, pronounced with the 30 second group, and drastic with the other groups. The 600 second group had the greatest suppressive effect operating. The suppression effect did not appear to be due to tissue damage inasmuch as most of the experimental rats (except the 600 seconds one) convulsed again at previous low ETI levels following a 15 or 16 day rest at the end of the experiment. This result suggests that the suppression effect is a relatively transient event.
The generalized convulsive seizure state induced by daily electrical stimulation of the amygdala in split brain cats
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