Therapeutic Effect Of Low-frequency Electrical Stimulation At The External Globus Pallidus On Epilepsy In Rats And Its Potential Mechanisms

BackgroundEpilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. Nearly ten million people have epilepsy in China. Recurrent epileptic seizures may lead to accidents and chronic cognitive impairment. Because the complex pathogenesis of epilepsy still remains unclear, clinical treatment can not completely control seizures. Despite chronic medication therapy, more than 30% of patients will suffer from persistent seizures. A subset of these patients will be candidates for open surgery or stereotactic radiosurgery which still can be limited by anticipated functional deficits such as memory loss or cognitive impairment. Moreover, patients with seizures arising from eloquent cortex, or which are multiple focal, bilateral, or generalized, are not candidates for resective surgery. Therefore, treatment of intractable epilepsy remains one of the major problems in epilepsy research so that alternative therapeutic approaches are pressing needed.Deep brain stimulation (DBS) is emerging as a new and promising option for the treatment of intractable epilepsy with the advantages of reversibility, adjustability and low risk of complications. The Food and Drug Administration (FDA) approved DBS for parkinsonian, dystonia and depression. Success in managing these disorders with DBS has opened the door to its use in epilepsy. Evidence from both clinical and animal studies has demonstrated that DBS targeting specific brain areas in or outside of the epileptic foci acts against epileptic seizures or epileptogenesis. DBS using low frequency stimulation (LFS) is thought to be relatively more promising than high frequency stimulation (HFS) as repeated HFS may be ineffective and even aggravate seizures. However, the mechanisms underlying DBS treatment for epilepsy remain unclear and the optimal stimulation protocols are therefore controversial and worthy of research. The target and frequency of stimulation have been considered as crucial factors.The external globus pallidus (GPe) is an integrative hub for coordinating neuronal activity across the basal ganglia (BG) circuits. It is a relatively large nucleus. The GPe is an important part of the corticothalamic circuit which is believed to participate in seizure propagation. Besides, regional atrophy in the bilateral globus pallidus were found in idiopathic generalized epilepsy. Furthermore, the GPe is mainly composed of GABAergic neurons. Therefore GPe might be a promising target of DBS for interfering with epilepsy.So we first investigate the effects of LFS and HFS targeting the GPe on seizures generated by amygdaloid kindling, maximal electroshock (MES) and amygdaloid-kindled seizures.The mechanisms underlying DBS treatment for epilepsy remain unclear. EEG background activity is one of the important markers for diagnosis of neuropsychiatric disorders. EEG of epileptic patients tend to have more obvious changes. Some special changes may be aura of epilepsy. Previous studies found that the δ rhythm (delta, 0.5-4Hz)、θ rhythm (theta,4-8Hz) and y rhythm (gamma,30-100Hz) have specific characters in epilepsy. Thus, we suppose DBS GPe may play different roles by interving with these specific rhythms. On the other hand, epilepsy is considered to be a network disorder. Epileptic networks include both the seizure focus and the remote brain structures. The corticothalamic circuit is believed to participate in seizure propagation. The current view is that DBS may work by by regulating neural circuits. Currently, two primary mechanistic theories of DBS have been promoted:suppression or activation of the targeted deep brain structure. As GPe is an important part of corticothalamic circuit, LFS GPe may interfere with the generation and propagation of epilepsy by affecting neuronal activities of GPe and relative circuits.Therefore, we further observed the effects of LFS and HFS on the EEG activity during kindling acquisition. We also investigate the effect of single pulse stimulation and LFS at GPe on neuronal activities.Part 1 Therapeutic effect of low-frequency electrical stimulation at the external globus pallidus on epilepsy in ratsLFS at the GPe immediately after the cessation of kindling stimulation slowed the progression of seizure stages and shortened the corresponding ADD during kindling acquisition. LFS increased the number of stimulations required to reach stages 1-3, this was mainly due to an increase in the number of days remaining in stage 0 and 1 compared with the Control. Meanwhile, LFS decreased the incidence of GS, suppressed the average stage, shortened the cumulative ADD and GSD, increased the average GS latency in fully kindled models. Also, LFS suppressed the average seizure stage and shortened tonic hindlimb extension durations on MES-induced seizures. However, HFS had no effect but reduced the number of stimulations needed to reach stage 4-5 and the number of days remaining in stage 2 was decreased. Besides, LFS GPe had no influence on normal motor activities of rats during our study. These results suggest that the GPe may be a potential and effective stimulus target of LFS.Part 2 The potential mechanism of the antiepileptic effect of low-frequency stimulation at the GPeEEG background activities analysis showed that delta power increased during amygdala kindling acquisition. LFS of the GPe reversed the increase of delta power during kindling acquisition. This parameter is considered to be an EEG marker of the epileptic focus. HFS GPe had no such effect on delta power. These results suggest that DBS GPe may play different roles by interving with delta rhythm. On the other hand, we found that both single pulse stimulation and low-frequency stimulation at GPe can increase GPe neuronal firing.In conclusion, we found that LFS of the GPe has therapeutic effects on epileptogenesis, generalized seizures and MES induced seizures. EEG analysis showed that LFS of the GPe reversed the increase of delta power which is considered to be an EEG marker of the epileptic focus during kindling acquisition. We also provide direct evidence that LFS of the GPe increase GPe neuronal firing. These results suggest that the GPe may be a potential and effective stimulus target of LFS. Besides, the difference between the effect of HFS and LFS targeting GPe open a new door to further research of DBS mechanisms. Our results also suggest that various targets may need specific stimulus frequency to inhibit epilepsy.