Cortical seizures following cerebellar stimulation in primates.

The effects of cerebellar stimulation were studied in monkeys with chronic alumina-cream epileptogenic foci in motor cortex. Low-frequency stimulation (5-15 c/sec) was ineffective in altering spontaneous cortical spiking. Clinical and electrographic seizures were elicited following high-frequency cerebellar stimulation (100 c/sec). This was a consistent finding following cerebellar stimulation, although no spontaneous seizures had been seen in these animals. These studies suggest the existence of facilitatory cerebellar mechanisms and indicate the need for further studies in chronic animal models.     

Role of the Fastigial Nucleus in Generalized Seizures as Demonstrated by GABA Agonist Microinjections

The cerebellum is electrically and metaboli cally active during seizures. Numerous studies have also shown that cerebellar electrical stimulation and lesions of the cerebellar cortex or nuclei influence seizure thresh old, but there are significant contradictions, with different effects observed even in investigations using the same species and similar seizure types and experimental ma nipulations. Discrete intracerebral microinjection of neu roactive agents has been used to characterize the way in which other brain regions control seizures, but has not been applied to the cerebellar systems. This approach has advantages because effects are restricted to specific re ceptors and spare passing axons; experimental variables also can be simply specified and reproduced. We used this method to characterize the role of the cerebellar nu clei in seizures and to determine if observed effects could be reproduced with different agents at different doses. Effects of bilateral control microinjections in the fastigial (medial) cerebellar nucleus were compared with different doses of the GABA_A agonist piperidine-4-sulfonic acid and the GABA_B agonist (?)baclofen (Bf). Soon after in jection, the animals were ataxic. After 4 min, seizures were induced by timed continuous intravenous (i.v.) bicu culline (BIC) infusion. Both GABA agonists produced significant reductions in myoclonic, clonic, and tonic sei zure thresholds. Injections just dorsal or anterior to this nucleus and bilateral dentate (lateral) nucleus injections had little effect on seizures. These results demonstrate that the cerebellar system does control seizures, but does not provide support for the early concept that cerebellar stimulation and systemic phenytoin block seizures through inhibition of cerebellar nuclei secondary to Pur kinje cell activation.     

Effects of Vagal Stimulation on Experimentally Induced Seizures in Rats

Summary: Repetitive stimulation of the vagus nerve inhibits chemically induced seizures in dogs. We report here the results and conclusions from studies designed to answer some of the immediate questions raised by this finding. (1) Maximal stimulation of vagal C fibers at frequencies greater than 4 Hz prevents or reduces chemically and electrically induced seizures in young male rats. (2) Antiepileptic potency is directly related to the fraction of vagal C fibers stimulated. (3) Vagal stimulation shortens but does not shut down a chemical seizure once it has begun. (4) In rats, optimal stimulus frequency is approximately 10–20 Hz; duration of stimulus, 0.5-1 ms; and stimulus strength, 0.2-0.5 mA/mm² of nerve cross-section. These results, when taken together with similar results obtained from dogs, monkeys, and humans, strongly suggest that periodic stimulation of the vagus nerve using appropriate stimulation parameters is a powerful method for preventing seizures. The data from the literature suggest that the antiepileptic actions of vagal stimulation are largely mediated by widespread release of GAB A and glycine in the brainstem and cerebral cortex. The probable pathway is via projections from the nucleus of the solitary tract to the reticular formation and thence by diffuse projections to the cortex and other areas. Intermittent vagal stimulation has the potentiality of reducing the number and/or the intensity of seizures in patients with intractable epilepsy. These results indicate that feasibility studies in humans should be continued and expanded.     

Chronic epileptic foci in monkeys: correlation between seizure frequency and proportion of pacemaker epileptic neurons.

A total of 1,802 neurons from 15 alert, undrugged Macaca mulatta monkeys were studied. Thirteen monkeys had chronic epilepsy induced by subpial alumina injections in precentral cortex. Precentral neurons were judged epileptic by the magnitude and variability of the percentage of interspike intervals less than 5 msec during periods when the monkeys were awake. This method of quantifying epileptic single neuron activity appears highly reliable in distinguishing epileptic neurons from precentral neurons in either normal cortex, cortex contralateral to, or within the focus. For the 13 epileptic monkeys, the relative proportion of strongly epileptic neurons found within foci was logarithmically correlated with the mean number of daily seizures. Because of the similarity between the physiology of the alumina focus in monkeys and epileptic foci in humans, these data imply that the severity of focal human epilepsy is a function of epileptic neuronal mass.     

Isoniazid induced seizures and cerebral cortical and cerebellar energy metabolism

Isoniazid is a useful chemical convulsant in that metabolic events associated with the preseizure state can be easily examined. In the present study, net levels of glucose, glycogen, ATP, and phosphocreatine were measured using enzymatic techniques in control mice, and in those injected with isoniazid. Results from this study showed a differential effect of isoniazid on cells from the cerebral cortex and the cerebellum. In the preseizure stage, the high energy phosphates ATP and phosphocreatine were decreased in layer 1 and the pyramidal cell layer of the cerebral parietal cortex, but were unchanged in the cerebellum. At the onset of seizures, metabolites were decreased not only in cortical layers, but in the molecular layer and Purkinje cell rich layer of the cerebellum as well. The somewhat delayed response of the cerebellum emphasizes the differential nature of metabolism in various brain regions. Such a delay in cerebellar energy response to perturbation may be conducive to the seizure state. In another series of mice, either sodium valproate or clonazepam was administered prior to isoniazid, and metabolite studies repeated. Results showed that at a time when each anticonvulsant acted to eliminate overt seizure activity, the reduction in ATP and phosphocreatine was not as great as it was in seizing mice treated with isoniazid alone.     

Single-pulse stimulation of cerebellar nuclei stops epileptic thalamic activity

BackgroundEpileptic (absence) seizures in the cerebral cortex can be stopped by pharmacological and optogenetic stimulation of the cerebellar nuclei (CN) neurons that innervate the thalamus. However, it is unclear how such stimulation can modify underlying thalamo-cortical oscillations.HypothesisHere we tested whether rhythmic synchronized thalamo-cortical activity during absence seizures can be desynchronized by single-pulse optogenetic stimulation of CN neurons to stop seizure activity.MethodsWe performed simultaneous thalamic single-cell and electrocorticographical recordings in awake tottering mice, a genetic model of absence epilepsy, to investigate the rhythmicity and synchronicity. Furthermore, we tested interictally the impact of single-pulse optogenetic CN stimulation on thalamic and cortical recordings.ResultsWe show that thalamic firing is highly rhythmic and synchronized with cortical spike-and-wave discharges during absence seizures and that this phase-locked activity can be desynchronized upon single-pulse optogenetic stimulation of CN neurons. Notably, this stimulation of CN neurons was more effective in stopping seizures than direct, focal stimulation of groups of afferents innervating the thalamus. During interictal periods, CN stimulation evoked reliable but heterogeneous responses in thalamic cells in that they could show an increase or decrease in firing rate at various latencies, bi-phasic responses with an initial excitatory and subsequent inhibitory response, or no response at all.ConclusionOur data indicate that stimulation of CN neurons and their fibers in thalamus evokes differential effects in its downstream pathways and desynchronizes phase-locked thalamic neuronal firing during seizures, revealing a neurobiological mechanism that may explain how cerebellar stimulation can stop seizures.     

The cerebellum and cognition: cerebellar lesions do not impair spatial working memory or visual associative learning in monkeys

Anatomical studies in non-human primates have shown that the cerebellum has prominent connections with the dorsal, but not the ventral, visual pathways of the cerebral cortex. Recently, it has been shown that the dorsolateral prefrontal cortex (DPFC) and cerebellum are interconnected in monkeys. This has been cited in support of the view that the cerebellum may be involved in cognitive functions, e.g. working memory. Six monkeys (Macaca fascicularis) were therefore trained on a classic test of working memory, the spatial delayed alternation (SDA) task, and also on a visual concurrent discrimination (VCD) task. Excitotoxic lesions were made in the lateral cerebellar nuclei, bilaterally, in three of the animals. When retested after surgery the lesioned animals were as quick to relearn both tasks as the remaining unoperated animals. However, when the response times (RT) for each task were directly compared, on the SDA task the monkeys with cerebellar lesions were relatively slow to decide where to respond. We argue that on the SDA task animals can prepare their responses between trials whereas this is not possible on the VCD task, and that the cerebellar lesions may disrupt this response preparation. We subsequently made bilateral lesions in the DPFC of the control animals and retested them on the SDA task. These monkeys failed to relearn the task. The results show that, unlike the dorsal prefrontal cortex, the cerebellum is not essential for working memory or the executive processes that are necessary for correct performance, though it may contribute to the preparation of responses.     

Double-blind, randomized controlled pilot study of bilateral cerebellar stimulation for treatment of intractable motor seizures

PURPOSE: The efficacy and safety of cerebellar stimulation (CS) was reevaluated in a double-blind, randomized controlled pilot study on five patients with medically refractory motor seizures, and especially generalized tonic-clonic seizures. METHODS: Bilateral modified four-contact plate electrodes were placed on the cerebellar superomedial surface through two suboccipital burr holes. The implanted programmable, battery-operated stimulator was adjusted to 2.0 microC/cm(2)/phase with the stimulator case as the anode; at this level, no patient experienced the stimulation. Patients served as their own controls, comparing their seizure frequency in preimplant basal phase (BL) of 3 months with the postimplant phases from 10 months to 4 years (average, eight epochs of 3 months each). During the month after implantation, the stimulators were not activated. The patient and the evaluator were blinded as to the next 3-month epoch, as to whether stimulation was used. The patients were randomized into two groups: three with the stimulator ON and two with the stimulator OFF. After a 4-month postimplantation period, all patients had their stimulator ON until the end of the study and beyond. Medication was maintained unchanged throughout the study. EEG paroxysmal discharges also were measured. RESULTS: Generalized tonic-clonic seizures: in the initial 3-month double-blind phase, two patients were monitored with the stimulation OFF; no change was found in the mean seizure rate (patient 1, 100%, and patient 5, 85%; mean, 93%), whereas the three patients with the stimulation initially ON had a reduction of seizures to 33% (patient 2, 21%; patient 3, 46%; patient 4, 32%) with a statistically significant difference between OFF and ON phase of p = 0.023. All five patients then were stimulated and monitored. At the end of the next 6 months of stimulation, the five patients had a mean seizure rate of 41% (14-75%) of the BL. The second patient developed an infection in the implanted system, which had to be removed after 11 months of stimulation; the seizures were being reduced with stimulation to a mean of one per month from a mean of 4.7 per month (BL level) before stimulation. At the end of 24 months, three patients were monitored with stimulation, resulting in a further reduction of seizures to 24% (11-38%). Tonic seizures: four patients had these seizures, which at 24 months were reduced to 43% (10-76%). Follow-up surgery was necessary in four patients because of infection in one patient and lead/electrode displacement needing repositioning in three patients. The statistical analysis showed a significant reduction in tonic-clonic seizures (p < 0.001) and tonic seizures (p < 0.05). CONCLUSIONS: The superomedial cerebellar cortex appears to be a significantly effective and safe target for electrical stimulation for decreasing motor seizures over the long term. The effect shows generalized tonic-clonic seizure reduction after 1-2 months and continues to decrease over the first 6 months and then maintains this effectiveness over the study period of 2 years and beyond.     

Chronic cerebellar stimulation in the monkey. Preliminary observations.

In a single monkey, the surface of the cerebellum was stimulated electrically for 205 hours with electrodes and parameter values similar to those currently used in humans for treatment of epilepsy. Im pedance of stimulating and nonstimulating control electrodes remained unchanged throughout an observation period of six months. Potentials evoked by cerebellar stimulation could be recorded from the cranium, providing a noninvasive technique of determining the level of current delivered to cerebellum. Examination of the implantation site showed marked meningeal thickening surrounding the stimulating electrodes. Such thickening was not observed surrounding a control set. Light and electron microscopical examination revealed severe loss of Purkinje cells in tissue near the stimulating electrodes. There was also a moderate loss in other parts of cerebellar cortex down to a depth of about 1 mm from the exposed surface. Biochemical analysis revealed metabolic abnormalities consistent with the morphologic evidence of widespread tissue damage.     

Frequency-dependent modulation of cerebellar excitability during the application of non-invasive alternating current stimulation

Backgroundit is well-known that the cerebellum is critical for the integrity of motor and cognitive actions. Applying non-invasive brain stimulation techniques over this region results in neurophysiological and behavioural changes, which have been associated with the modulation of cerebellar-cerebral cortex connectivity. Here, we investigated whether online application of cerebellar transcranial alternating current stimulation (tACS) results in changes to this pathway.Methodsthirteen healthy individuals participated in two sessions of cerebellar tACS delivered at different frequencies (5Hz and 50Hz). We used transcranial magnetic stimulation to measure cerebellar-motor cortex (M1) inhibition (CBI), short-intracortical inhibition (SICI) and short-afferent inhibition (SAI) before, during and after the application of tACS.Resultswe found that CBI was specifically strengthened during the application of 5Hz cerebellar tACS. No changes were detected immediately following the application of 5Hz stimulation, nor at any time point with 50Hz stimulation. We also found no changes to M1 intracortical circuits (i.e. SICI) or sensorimotor interaction (i.e. SAI), indicating that the effects of 5Hz tACS over the cerebellum are site-specific.Conclusionscerebellar tACS can modulate cerebellar excitability in a time- and frequency-dependent manner. Additionally, cerebellar tACS does not appear to induce any long-lasting effects (i.e. plasticity), suggesting that stimulation enhances oscillations within the cerebellum only throughout the stimulation period. As such, cerebellar tACS may have significant implications for diseases manifesting with abnormal cerebellar oscillatory activity and also for future behavioural studies.     

The role of transcranial magnetic stimulation in the study of cerebellar cognitive function

Transcranial magnetic stimulation (TMS) allows non-invasive stimulation of brain structures. This technique can be used either for stimulating the motor cortex, recording motor evoked potentials from peripheral muscles, or for modulating the excitability of other non-motor areas in order to establish their necessity for a given task. TMS of the cerebellum can give interesting insights on the cerebellar functions. Paired-TMS techniques, delivering stimuli over the cerebellum followed at various interstimulus intervals by stimuli over the motor cortex, allow studying the pattern of connectivity between the cerebellum and the contralateral motor cortex in physiological as well as in pathological conditions. Repetitive TMS, delivering trains of stimuli at different frequencies, allows interfering with the function of cerebellar circuits during the execution of cognitive tasks. This application complements neuropsychological and neuroimaging studies in the study of the cerebellar involvement in a number of cognitive operations, ranging from procedural memory, working memory and learning through observation.     

Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism

Clinical observations suggest that abnormalities within the cerebellum and/or the cerebellum--cholinergic forebrain connections may be key to explain the severe behavioral deficits and increases in seizures seen in autism. In order to explore functional relationships between brain areas implicated in many of the core behavioral features of autism, experiments utilizing animal models for specific autism-like behaviors have increased in recent years. In the current study, we used a rodent model for the autism-like behavior of environment exploration deficits to examine the role of the cerebellum and its connectivity to the forebrain. In addition, due to the possible common neural pathways between seizures and autism-like behaviors, we explored the possibility for limiting autism-like behaviors via antiseizure brainstem and cerebellar circuitry. In two experiments, adult male rats showed a significant decrease in exploration behavior following developmental cerebellar suction lesions (experiment 1) or i.c.v. saporin injections specifically targeting Purkinje cells, but not after the addition of saporin-induced cholinergic forebrain lesions (experiment 2). In both experiments, the anticonvulsant treatment of inhibition of the medullary nucleus tractus solitarius (NTS) restored exploration behavior to control levels. These findings suggest that specific neuronal populations within the cerebellum are responsible for mediating exploration behavior, and these neuronal populations are similar to the circuitry involved in limbic motor seizures in that they are sensitive to brainstem inhibition. Furthermore, these results suggest this connection could be utilized in order to control behavioral deficits seen in autism with treatments, such as vagal nerve stimulation, which are effective against pharmaco-resistant seizures.     

Antiepileptic Properties of Cerebrospinal Fluid After Activation of the Antiepileptic System of the Brain

Intraventricular injection of cerebrospinal fluid (CSF) obtained from cats with chronic electrical stimulation of cerebellar vermal cortex resulted in suppression of epileptic foci activity in cat brain cortex, an increase in time to first seizure, and weakening of generalized seizures in rats. The CSF obtained from cats after electroshock seizures induced less pronounced, although significant antiepileptic action in comparison with the CSF of cats with cerebellar stimulation on the model of generalized seizures in rats. The antiepileptic action of CSF obtained from cats with electrostimulation of cerebellar vermis and from electroshock cats is due to appearance of peptide factors in CSF.     

Resistance to propagation of amygdaloid kindling seizures in rats with genetic absence epilepsy

PURPOSE: The existence of absence epilepsy and temporal partial seizure pattern in the same patient is an uncommon state. In the present study, we aimed to evaluate whether the process of kindling as a model of complex partial seizures with secondary generalization is altered in rats with genetic absence epilepsy. METHODS: Six- to 12-month-old nonepileptic control Wistar rats and genetic absence epileptic rats from Strasbourg (GAERS) were used in the experiments. One week before the experiments, bilateral stimulation and recording electrodes were implanted stereotaxically into the basolateral amygdala and cortex, respectively. Animals were stimulated at their afterdischarge threshold current twice daily for the process of kindling and accepted as fully kindled after the occurrence of five grade 5 seizures. Bilateral EEGs from amygdala and cortex were recorded continuously during 20 min before and 40 min after each stimulus. RESULTS: All control Wistar rats were fully kindled after stimulus 12 to 15. Although the maximal number of stimulations had been applied, GAERS remained at stage 2, and no motor seizures were observed. The afterdischarge duration in bilateral amygdala and the cortex after the kindling stimulus was shorter in GAERS when compared with control rats. CONCLUSIONS: Occurrence of only grade 2 seizures and no observation of grade 3-5 seizures in GAERS with the maximal number of stimulations would suggest that the generalized absence seizures may be the reason of the resistance in the secondary generalization of limbic seizures during amygdala kindling.     

Effect of Chronic Electrical Stimulation of the Centromedian Thalamic Nuclei on Various Intractable Seizure Patterns: I. Clinical Seizures and Paroxysmal EEG Activity

Twenty-three patients with various intractable seizure patterns were divided into four groups based on their most frequent seizure type and their clinical and EEG response to chronic electrical stimulation of the centromedian thalamic nuclei (ESCM): group A, generalized tonic-clonic (GTC, n = 9); group B, partial motor (Rasmussen type) (n = 3); group C, complex partial seizures (CPS, n = 5); and group D, generalized tonic seizures (Lennox-Gastaut type) (n = 6). CM were radiologically and electrophysiologically localized by means of stereotaxic landmarks and by thalamically induced scalp recruitinglike responses and desynchronization. ESCM consisted of daily 2-h stimulation sessions for 3 months. Each stimulus consisted of a 1-min train of square pulses with a 4-min interstimulus interval, alternating right and left CM. Each pulse was 1.0 ms in duration at 60/s frequency and 8–15 V (400–1,250 μ-A) amplitude. Voltage (V), current flow (μA) and impedance (kΩ) at the electrode tips were kept constant. A significant decrease in the number of seizures per month and paroxysmal EEG waves per 10-s epochs occurred in group A patients between the baseline period (BL) and the ESCM period. These changes persisted for >3 months after discontinuation of ESCM (poststimulation period, Post). Post was accompanied by a significant decrease in the number of paroxysmal EEG discharges. A substantial decrease in seizures and paroxysmal discharges was also observed in patients of group B. In contrast, patients of groups C and D showed no significant changes from BL to ESCM and Post periods, except for a significant decrease in the number of seizures in group D patients from BL to Post periods.     

The cerebellothalamocortical pathway in essential tremor

The cerebellum is implicated in the pathogenesis of essential tremor (ET). The authors examined the excitability of the cerebellothalamocortical pathway in ET and found it to be normal. Tremor reset occurred with motor cortex stimulation but not with cerebellar stimulation. These findings suggest that the abnormal oscillatory activity in ET does not originate in the cerebellar cortex but are consistent with the abnormal activity being transmitted through the cerebellothalamocortical pathway being driven by abnormal cerebellar afferent input from areas such as the inferior olive.     

Involvement of Proprioceptive Feedback in Brainstem-Triggered Convulsions

Summary: Purpose : In rodents, specific motor components of generalized convulsive seizures depend on two distinct anatomic substrates: (a) forebrain networks are responsible for facial and forelimb clonus with or without rearing and falling; and (b) brainstem networks are responsible for running-bouncing fits and tonic convulsions. To investigate the requirement of proprioceptive inputs in the generation of these two different types of seizures, we compared the effects of neuromuscular blockade by D-tubocurarine on the EEG expression of brainstem and forebrain-triggered seizures.
Methods : Unilateral electrical stimulations were applied for 50 consecutive days in freely moving male adult rats through a bipolar electrode aimed at the dorsal hippocampus (n = S), the occipital cortex (n = 4), the inferior colliculus (n = 6), or the midbrain reticular formation (n = 6). Two days after the last stimulation, rats were paralyzed with d-tubocurarine and stimulated in the same way.
Results : In brainstem structures, the first electrical stimulation induced tonic seizures concomitant with low-voltage cortical activity; repetition of daily stimulations progressively induced tonic-clonic seizures associated with high-amplitude cortical spike-wave discharges. After immobilization by d-tubocurarine, brainstem stimulations failed to induce any EEG paroxysm. In forebrain structures, repeated electrical stimulations produced a classic kindling with progressive occurrence of clonic seizures associated with large cortical discharges; d-tubocurarine left unchanged the EEG pattern of these latter seizures.
Conclusions : These data suggest that proprioceptive reafferentation resulting from movement is necessary for the generation of self-sustained brainstem seizures but is not implicated in the elaboration of forebrain seizures.     

Effects of cerebellar and brain stem stimulation on hippocampal formation neurons in the monkey

Micro- and macroelectrode recording techniques were used to detect the presence of cerebellar influences on electrical activity in the hippocampal formation of the rhesus monkey. Only 2% of the cells studied responded to cerebellar stimulation. These responsive cells showed a decreased firing rate. No evoked potentials were detected after cerebellar stimulation in any of the monkeys. The effects of brain stem stimulation were tested in two monkeys. One electrode placement lateral to the central gray did not evoke any neuronal responses. The other, situated in the raphe nucleus near the border of the dorsal raphe and nucleus centralis superior, evoked inhibitory responses in 17% of the cells tested. These results (i) fail to provide support for the existence of an important pathway from the cerebellum to the hippocampal formation in monkeys, and (ii) preliminarily extend to a primate species previous results in rat and cat showing an inhibitory effect of raphe stimulation on hippocampal neurons.     

Psychological effects of short term cerebellar stimulation in epilepsy.

The effects of short term cerebellar stimulation on integrative functions as measured by standardized psychological tests were studied. The patient group consisted of 12 epilepsy patients undergoing chronic cerebellar stimulation as treatment for intractable seizures. Three comparison groups included nonstimulated epilepsy patients, stimulated cerebral palsy patients, and stimulated stroke patients. Cerebellar stimulation resulted in some alterations in test performance. Improvements occurred from first to second test administration for both stimulated and nonstimulated subjects, as a probable practice effect. Short term stimulation of the cerebellar cortex does not result in apparent deficits. However, significant improvement in verbal output and in visual-motor performance occurred for the stimulated epilepsy group along with a small decrement in sustained concentration in a numerical task. Preliminary hypotheses were offered to explain the results.     

Hemifacial seizures due to ganglioglioma of cerebellum

We present a male infant with hemifacial seizures refractory to antiepileptic medication. Hemifacial spasms around the left eye were frequent during wakefulness and sleep since birth. He also had mild psychomotor retardation. Magnetic resonance imaging (MRI) revealed a large tumor in the left middle cerebellar peduncle. Ictal single photon emission computed tomography (SPECT) and ictal ¹⁸F-fluorodeoxyglucose [¹⁸F-FDG] positron emission tomography (PET) revealed hyperperfusion and hyper glucose metabolism at the tumor. Total removal of the tumor resulted in complete disappearance of hemifacial seizures and improved psychomotor development, indicating that the cerebellar tumor caused hemifacial seizures. A histopathological study confirmed that the tumor was a ganglioglioma. This case and the literature on similar cases indicated that this was a new epileptic syndrome originating in the cerebellum. Early diagnosis and early complete removal of the epileptogenic lesion should be recommended for this syndrome.