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Brain Research 1010 (2004) 151 – 155 Stimulation of the superior cerebellar peduncle during the development of amygdaloid kindling in rats Carmen Rubioa, Vero´nica Custodioa, Francisco Jua´rezb, Carlos Paza,* a Departamento de Neurofisiologı´a, Instituto Nacional de Neurologı´a y Neurocirugı´a M.V.S., Insurgentes Sur 3877, Mexico 14269 D.F., Mexico b Instituto Nacional de Psiquiatrı´a R.F., Mexico Accepted 2 March 2004 Cerebellar manipulations have been used successfully in some intractable epileptic patients, however, their intrinsic mechanisms are not fully understood. To further clarify the cerebellar participation in epilepsy, we stimulated 10 rats with 100 Hz, 20 AA at the superior cerebellarpeduncle (SCP) during amygdaloid kindling. Results were compared to 10 rats with an electrode placed at the SCP without stimulation and10 rats without electrodes at the SCP used as control. We found that SCP stimulation increased the theta and alpha rhythms at thecontralateral motor cortex. Such a stimulation produced hypertonicity of the forelimbs and tremor of the head. In this condition, we found thateach of the behavioral stages during amygdaloid kindling in the SCP stimulated rats was reached earlier, while the amygdaloid electrographicafterdischarges (ADs) were longer during the first and shorter in the final trials as compared to controls. Moreover, amygdaloid ADs recordedexclusively during the behavioral stage-5 were significantly shorter than those recorded in the control conditions. We suggest that SCPstimulation could change the customary electrographic and convulsive expression of amygdala kindling in such a manner as to initiallyfacilitate the limbic seizures and impede the secondary generalized seizures.
D 2004 Elsevier B.V. All rights reserved.
Theme: Disorders of the nervous systemTopic: Epilepsy, basic mechanisms Keywords: Epilepsy; Kindling; Cerebellum; Power spectra; Amygdaloid afterdischarge scharges (ADs) and the secondary generalized seizuresprovoked by kindling stimulation Some clinical improvement in epileptic patients submit- Kindling has been referred to as a progressive develop- ted to cerebellar electrical stimulation suggests that the ment of electroencephalographic and behavioral seizures cerebellum participates in epileptic activity Exper- produced by repeated application of low-intensity electrical imentally, cerebellar cortical stimulation in cats results in a stimulation to discrete forebrain structures resulting in significant decrease on epileptic like activity produced by secondary generalized seizures However, it is not clear systemic or cortical penicillin applications Electri- how the lengthening of the amygdaloid ADs could be cal stimulation of the cerebellar dentate nucleus decreases related to the development of kindling. Nevertheless, the the epileptic activity produced by systemic penicillin appli- fact that repetition of the stimulation that initially produced cation in rats and by cortical penicillin application in local ADs results in the eventual development of general- anesthetized cats On the contrary, total cerebellectomy ized convulsion suggests that progressive recruitment of magnifies the epileptic activity produced by cortical peni- related cerebral structures underlies this phenomenon.
cillin stimulation in anesthetized rats and increases the Moreover, It has also been reported that lesions of the duration of both the amygdaloid electrographic afterdi- cerebellum shortened the mean duration of the amygdaloidADs using the kindling stimulation In this view,other sites within the brain would not only contribute in * Corresponding author. Tel.: +55-56063822x2021; fax: +55- propagation of seizure activity but would also participate in E-mail address: (C. Paz).
a reverberatory network that helps to maintain the AD 0006-8993/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainres.2004.03.015 C. Rubio et al. / Brain Research 1010 (2004) 151–155 duration at the site of stimulation. Thus, to further under- amygdaloid AD was attained. On each subsequent trials, the stand the cerebellar participation in epilepsy, we assessed intensity required to generate amygdaloid ADs was applied the amygdaloid AD during the kindling in rats with changes daily until 10 stage-5 seizures were obtained. During the in the EEG power spectra produced by the electrical search of the amygdaloid response the SCP was not stim- stimulation of the superior cerebellar peduncle (SCP).
ulated, though once the kindling study began the SCPstimulation was applied from 10 s before amygdaloidstimulation until 10 s after termination of the AD.
Once the best SCP and amygdaloid stimulation param- eters were determined, amygdaloid kindling was studied in Thirty male Wistar rats weighing 280 – 310 g were three different groups: (a) 10 rats with an electrode placed handled daily and kept under controlled environmental over the left SCP with no stimulation; (b) 10 rats with an conditions (20 – 23 jC and 12/12-h light/dark cycle) for at electrode in the left SCP and electrical stimulation (100 Hz, least 2 weeks before surgery. Seven days later, the rats were 20 AA); and (c) 10 rats without electrodes at the SCP used as anesthetized (Ketamine, 100 mg/kg, i.p.) and placed on a the control group. During kindling, the following parame- stereotaxic apparatus in order to conduct bipolar electrodes ters were measured: (a) duration of the amygdaloid AD for stimulation and recording in the left basolateral amyg- regardless of the behavioral stage progression; (b) duration daloid nucleus (coordinates: anterior 6.2 mm, lateral 5.0 of the amygdaloid AD recorded during 10 consecutive mm, height 1.5 mm using the interaural line as a reference stage-5 seizures; and (c) the number of trials required to point), and in the right sensory-motor cortex to record the reach each of the behavioral stages following Racine's secondary EEG activity. Twenty rats were chosen for further criteria Briefly: Stage-1 mouth and facial movements, electrode implantation over the left SCP (coordinates: ante- Stage-2 head nodding, Stage-3 forelimb clonus, Stage-4 1.0 mm, lateral 2.0 mm, height 1.5 mm). Electrodes rearing, Stage-5 rearing and falling.
were led to their loci using the Paxinos' and Watson's We applied a Student's t-test in those conditions where stereotaxic atlas Each electrode consisted of two the absolute power analysis was used with an accepted twisted insulated wires (0.005-in. diameter) made of stain- nominal level of significance of p<0.02. The number of less steel and coated with teflon except for the tips. A screw trials to reach each of the behavioral stages and the duration implanted in the skull served as an indifferent source of of amygdaloid AD during kindling and during 10 stage-5 reference. Electrodes were arranged and soldered to a mini- seizures were compared between groups using a one-way connector and secured to the skull with dental acrylic. Skin analysis of variance (ANOVA) followed by a Tukey test cuts were sutured while exposing the mini-connector.
with an accepted nominal level of significance of p<0.01.
After 10 days of post-operative recovery, the rats were The amygdaloid AD duration was analyzed until the 18th placed in a soundproof chamber while their mini-connectors trial because some groups were incomplete since some rats were connected to a 78D Grass polygraph via flexible reach 10 stage-5 seizures earlier. Once electrographic cables. Electrographic activity records were stored and recordings were concluded, rats were deeply anesthetized digitized in a 486 PC computer provided with software and intracardiacally perfused with isotonic saline solution from Stellate Systems that could discriminate between followed by 10% formalin. After keeping the brains for 30 different bands using fast Fourier transform language.
Electrographic activity was assessed using an absolutepower analysis extracted in three frequency bands as sug-gested by Kubicki et al. (theta, 3.5 – 7.5 Hz; alpha 7.5 –12.0 Hz; beta 12.0 – 30.0 Hz).
Once ordinary electrographic activity was determined, the stimulation parameters to obtain cerebellar or amygda-loid responses were selected. For this purpose, all rats withelectrodes over the SCP were stimulated at 1-h intervalsusing 0.5-ms rectangular pulses at a frequency of 1, 10 or100 Hz each with 10, 15 or 20 AA until a behavioral orelectrographic changes in the absolute power analysis wasproduced. Amygdala stimulation parameters were deter-mined when an electrographical response was produced(amygdaloid AD). Initially, 0.5-ms rectangular pulses at Fig. 1. Absolute power bands comparing EEG activity before (white bars) 60 Hz for 1 s with an intensity of 5 V were employed using and after SCP stimulation (gray bars) extracted in three different frequency an electronic circuit breaker device which permitted us to bands: (theta 3.5 – 7.5 Hz, alpha 7.5 – 12.0 Hz, and beta 12.0 – 30.0 Hz).
record and stimulate through the same electrode If a Values are expressed as means F S.E.M. in AV2 during SCP stimulation response was not elicited, the intensity of the stimulation with 100 Hz 20 AA. Statistical differences were analyzed using Student's t- was increased in 1 V on subsequent stimulation until one test, *p<0.02.

C. Rubio et al. / Brain Research 1010 (2004) 151–155 Fig. 2. Number of trials required to reach each kindling stage according to Fig. 4. Ten consecutive amygdaloid ADs recorded during stage-5 seizures Racine et al. Bars indicate means F S.E.M. for the control group for the control group (black circles), rats with an electrode over the SCP (black bars), with an electrode over the SCP without stimulation (gray bars) without stimulation (gray circles) and rats stimulated with 20 AV at 100 Hz and with left SCP stimulation (white bars). Statistical differences were over the left SCP (white circles). Significant differences were found using evaluated for each stage using a one-way ANOVA with a significance of the ANOVA test ( p<0.001), though only the SCP stimulated rats showed p<0.01, followed by a Tukey test within groups *p<0.01.
significant differences within groups using the Tukey test (ap<0.01).
days in 10% formalin, the mesencephalon and pyriform lobe ioral or electrocorticographic changes with light SCP stim- were coronally or sagittally sliced in 8-Am serial sections ulation, though on the whole they showed the clearest and stained using the Klu¨ver – Barrera technique in order to response with the highest frequency and intensity of stim- verify the correct position of the electrodes.
ulation. Therefore, the highest parameters were chosen totest the possible effects of SCP stimulation during thedevelopment of amygdaloid kindling.
We found significant differences between groups in the number of trials required to reach each of the behavioral We stimulated the SCP with the highest frequency and stages. When comparison was done within groups, rats intensity (100 Hz and 20 AA) and found a significant stimulated at the SCP required fewer trials to reach each increased in theta and alpha rhythms In this of the behavioral stages conditions, we found that the SCP stimulation elicited alight hypertonicity of the forelimbs in addition to a slightand quick tremor of the head. When the animals moved, gaitwas characterized by ataxia. Some animals showed behav- Fig. 3. Temporal evolution of the amygdaloid AD duration for the controlgroup (black circles), rats with an electrode over the left SCP withoutstimulation (gray circles) and rats stimulated at the left SCP (white circles).
Fig. 5. Low-power amplification of coronal (A) and sagittal (B) sections at Data are expressed as means F S.E.M. After a comparison between groups the mesencephalum and cerebellum (CB) showing the track of the bipolar using the ANOVA test ( p<0.01), rats stimulated at the SCP showed either electrodes (E) placed on the superior cerebellar peduncle (SCP). Closely the longest or shortest AD duration when compared within groups using the situated structures like the locus coeruleus (LC), mesencephalic trigeminal Tukey test, ap<0.01. Non-stimulated rats also showed shorter AD duration nucleus (Me5), fourth ventricle (4V), inferior colliculus (IC) and choroids as compared to control, bp<0.01.
plexus (ChP) are indicated.
C. Rubio et al. / Brain Research 1010 (2004) 151–155 Significant differences were found from the first to the structures and fibers other than the dentate and interpositus 7th but not the 4th trials ( F2,27=4.94, 4.85, 6.14, 10.54, forebrain pathways. However, we excluded the possibility 4.75, 5.26; p<0.01) and from the 14th to the 18th trials that the stimulation of the SCP could reach the midbrain ( F2,27=8.73, 40.01, 64.62, 49.22, 46.48; p<0.01) when reticular formation, because we found an increase in slow compared to the amygdaloid AD duration between groups.
wave bands instead of the classical arousal response medi- Comparisons within groups (Tukey) indicate that the group ated via reticulo- thalamo-cortical pathway The SCP of rats stimulated at the SCP showed the longest AD also includes fibers from the locus ceruleus though we duration at the 3rd, 5th, 6th and 7th trials, though this group discarded its possible participation in our results because the also showed the shortest from the 14th to the 18th trials stimulation of this structure significantly delays the appear- when compared to control and non-stimulated groups.
ance of stage-5 seizures, contrary to our findings The Additionally, rats with electrodes at the SCP without stim- parabrachial nuclei show a remarkable c-fos expression ulation during kindling also showed shorter ADs duration at associated with seizures that occur in genetically epilepsy- the 15th, 16th and 17th trials when compared to the control prone rats or produced by thalamic microinjections of carbachol However, c-fos expression has also been We found significant differences between groups ( F2,27= found throughout the brain using these experimental models 37.80, 49.10, 42.07, 70.72, 63.53, 43.79, 9.43, 29.82, 18.01, of epilepsy and a direct participation of the parabrachial 47.14; p<0.001) when compared to 10 consecutive stage-5 nuclei has not been related to amygdaloid kindling.
seizures. However, only the SCP stimulated rats showed We found that each of the behavioral stages in SCP significant differences within groups The EEG stimulated rats was reached earlier, while the amygdaloid changes induced in the motor cortex by SCP stimulation ADs were longer during the first seizures and shorter during indicate the accuracy of electrode placement, which was the last as compared to the control group. However, sec- further confirmed histologically tioning of the left SCP done 1 week before the beginning ofthe kindling stimulation did not interfere with the typicalstage progression, though the amygdaloid AD durations recorded in kindled rats were significantly shorter We do not know how the cortical EEG activity could be Most experimental models of epilepsy show considerable after the SCP lesions. Nevertheless, we suppose that its controversy regarding the role of the cerebellum in seizures.
effects on the EEG activity could vary with time and cannot On account of such differences, we only compared results be compared to those SCP stimulations applied simulta- where the kindling model was used. We found that the neously with the amygdaloid stimulation. Decreases in lengthening of the amygdaloid ADs and the development of glutamate, aspartate and GABA were detected on the 7th the behavioral seizures in rats without electrodes at the SCP day after cerebellectomy in the thalamus and on the 15th occurred as have been previously described by others day in the cerebral cortex and both areas showed a total However, we found that the mere presence recovery at the 30th day The participation of the of an electrode at the SCP without electrical stimulation cerebellum directly over the cerebral cortex has also been restricts expression of secondarily generalized seizures. We studied using the kindling paradigm. Lesions in the lateral believe that such restriction could be due to a potential thalamus or the red nucleus and SCP abolished the tonic damage produced by the electrode as has been previously component of the seizures produced by neocortical kindling found in rats with SCP lesions Nevertheless, the most However, kindling from neocortical areas differed outstanding effect was found when SCP electrical stimula- substantially from amygdaloid kindling, specifically the tion, besides the motor upset, initially facilitated the devel- ADs remained relatively steady along subsequent stimula- opment of kindling but later prevented the secondary tions while behavioral convulsions occurred according to generalization of epileptic seizures. Similar motor impair- the stimulated neocortical area ments have also been reported by electrical stimulation of The cerebellar dentate and interpositus nuclei innervate the dentate nucleus or by deep cerebellar lesions thalamic neurons, which in turn project to the amygdaloid Then, we hypothesize that the SCP stimulation complex. It is known that the dentate and interpositus nuclei could exert a blocking effect over the SCP in such a way send efferents to the parafascicular and ventromedial tha- that the dentate and interpositus efferents remain temporally lamic nuclei Such thalamic nuclei are anatomically related to the ipsilateral amygdala Thus, SCP stimula- Several behavioral and electrographic manifestations tion inducing cortical electrographic changes through their observed in cerebellar lesions are the result of damage to thalamic relays could participate in increasing the AD extra-nuclear structures rather than to the nuclei themselves.
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