Stimulation Of Thalamic Nuclei Research Articles

Deep Brain Stimulation of Bilateral Centromedian Thalamic Nuclei in Pediatric Patients with Lennox-Gastaut Syndrome: An Institutional Experience

IntroductionSurgical management of pediatric patients with non-lesional, drug-resistant epilepsy (DRE), including patients with Lennox-Gastaut Syndrome (LGS), remains a challenge given the lack of resective targets in most patients, and demonstrates seizure freedom rates <50% at 5-years. The efficacy of deep brain stimulation (DBS) is less certain in children than adults. This study examined clinical and seizure outcomes for pediatric patients with LGS undergoing DBS targeting of the centromedian thalamic nuclei (CMTN). MethodsIRB-approved retrospective analysis of patients ≤19-years with clinical diagnosis of LGS undergoing bilateral DBS placement to the CMTN from 2020-2021 by a single surgeon. ResultsFour females and 2 males, aged 6-19 years were identified. Before surgery, each child experienced at least 6-years of refractory seizures; 4 children experienced seizures since infancy. All took antiseizure medications at time of surgery. Five children had prior placement of a vagus nerve stimulator, 2 had previous corpus callosotomy. Mean length of stay following DBS was 2-days. No children experienced adverse neurological effects from implantation; mean follow-up time was 16.3 months. Four patients had >60% reduction in seizure frequency following surgery, 1 patient experienced 10% reduction, 1 patient demonstrated no change. No children reported worsening seizure symptoms post-surgery. ConclusionsOur study contributes to the sparse literature describing CMTN DBS for children with DRE from LGS. Our results suggest that CMTN DBS is a safe and effective therapeutic modality that should be considered as alternative or adjuvant therapy for this challenging patient population. Further studies with larger patient populations are warranted.

Stimulation of the pulvinar nucleus of the thalamus in epilepsy: A systematic review and individual patient data (IPD) analysis

Emerging neuromodulatory treatments, such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), have shown promise in reducing drug-resistant seizures. While centromedian thalamic nucleus and anterior thalamic nucleus stimulation have been effective in certain types of seizures, limited research has explored pulvinar nucleus stimulation for epilepsy. To address this gap, we conducted a systematic review and individual patient data analysis. Of 78 resultant articles, 5 studies with transient stimulation and chronic stimulation of the pulvinar nucleus were included. Of the 20 patients reviewed, 65% of patients had temporal lobe seizures, while 20% had temporooccipital/occipital lobe seizures. Transient stimulation studies via stereoelectroencephalography (SEEG) showed pulvinar evoked potential response rates of 80% in the mesial temporal region, 76% in the temporal neocortex, and 67% in the TP junction. Another study reported clinically less severe seizures in 62.5% of patients with pulvinar stimulation. In chronic stimulation studies, 80% of patients responded to RNS or DBS, and 2 of 4 patients experienced > 90% seizure reduction. The pulvinar nucleus of the thalamus emerges as a potential target for chronic stimulation in drug-resistant epilepsy. However, knowledge regarding pulvinar connectivity and chronic stimulation remains limited. Further research should investigate specific subregions of the pulvinar for epilepsy treatment. Understanding the role of pulvinar stimulation and its cortical connectivity will advance therapeutic interventions for epilepsy patients.

Ventral intermediate nucleus deep brain stimulation for treatment-resistant focal aware motor seizures: illustrative case.

Resection of the seizure onset zone (SOZ) is considered the gold standard for treating refractory focal aware seizures (FASs). When resective surgery is unadvisable, deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT; ANT-DBS) has been the procedure of choice. However, less than half of patients with FASs respond to ANT-DBS. The need for alternative targets to effectively treat FAS is thus evident. The authors report the case of a 39-year-old woman presenting with pharmaco-resistant focal aware motor seizures, with the SOZ located in the primary motor cortical area. She had previously undergone unsuccessful resection of the left temporoparietal operculum elsewhere. Considering the risk of new resective surgery, she was offered combined ventral intermediate nucleus (Vim)/ANT-DBS. Vim-DBS proved to be superior to ANT-DBS for seizure control (88% vs 32%), although the association of both provided the best results (97%). This is the first report on the use of the Vim as a target of DBS for the treatment of FAS. The excellent results were presumably obtained by modulation of the SOZ through Vim projections to the motor cortex. This opens a completely new avenue for treating FAS: chronic stimulation of specific thalamic nuclei.

Medial Pulvinar Stimulation in Temporal Lobe Epilepsy: A Literature Review and a Hypothesis Based on Neuroanatomical Findings.

While bilateral stimulation of the anterior thalamic nuclei remains the only approved deep brain stimulation (DBS) option for focal epilepsy, two additional thalamic targets have been proposed. Earlier work indicated the potential of centromedian thalamic nucleus stimulation with recent findings highlighting the medial pulvinar nucleus. The latter has been shown to exhibit electrophysiological and imaging alterations in patients with partial status epilepticus and temporal lobe epilepsy. On this basis, recent studies have begun assessing the feasibility and efficacy of pulvinar stimulation, with encouraging results on the reduction of seizure frequency and severity. Building on existing neuroanatomical knowledge, indicating that the medial pulvinar is connected to the temporal lobe via the temporopulvinar bundle of Arnold, we hypothesize that this is one of the routes through which medial pulvinar stimulation affects temporal lobe structures. We suggest that further anatomic, imaging, and electrophysiologic studies are warranted to deepen our understanding of the subject and guide future clinical applications.

Total intravenous anesthesia with remimazolam in a patient with epilepsy who underwent deep brain stimulation: a case report

Drugs administered for anesthesia can trigger seizure attacks in patients with epilepsy. Benzodiazepines have been consistently reported to be anticonvulsants, and a novel benzodiazepine, remimazolam, was recently introduced. We report a case of total intravenous anesthesia maintained with remimazolam in a patient with epilepsy who underwent deep brain stimulation of both anterior thalamic nuclei. Despite the administration of multiple anti-epileptic drugs, no tolerance to remimazolam was observed. Perioperative seizures were also not observed. Remimazolam can be considered the anesthetic of choice in patients with epilepsy.

In Vivo Super-Resolution Track-Density Imaging for Thalamic Nuclei Identification.

The development of novel techniques for the in vivo, non-invasive visualization and identification of thalamic nuclei has represented a major challenge for human neuroimaging research in the last decades. Thalamic nuclei have important implications in various key aspects of brain physiology and many of them show selective alterations in various neurologic and psychiatric disorders. In addition, both surgical stimulation and ablation of specific thalamic nuclei have been proven to be useful for the treatment of different neuropsychiatric diseases. The present work aimed at describing a novel protocol for histologically guided delineation of thalamic nuclei based on short-tracks track-density imaging (stTDI), which is an advanced imaging technique exploiting high angular resolution diffusion tractography to obtain super-resolved white matter maps. We demonstrated that this approach can identify up to 13 distinct thalamic nuclei bilaterally with very high inter-subject (ICC: 0.996, 95% CI: 0.993-0.998) and inter-rater (ICC:0.981; 95% CI:0.963-0.989) reliability, and that both subject-based and group-level thalamic parcellation show a fair share of similarity to a recent standard-space histological thalamic atlas. Finally, we showed that stTDI-derived thalamic maps can be successfully employed to study structural and functional connectivity of the thalamus and may have potential implications both for basic and translational research, as well as for presurgical planning purposes.

Effects of anterior thalamic nuclei stimulation on hippocampal activity: Chronic recording in a patient with drug-resistant focal epilepsy.

Implanted neurostimulation devices are gaining traction as palliative treatment options for certain forms of drug-resistant epilepsy, but clinical utility of these devices is hindered by incomplete mechanistic understanding of their therapeutic effects. Approved devices for anterior thalamic nuclei deep brain stimulation (ANT DBS) are thought to work at a network level, but limited sensing capability precludes characterization of neurophysiological effects outside the thalamus. Here, we describe a patient with drug-resistant temporal lobe epilepsy who was implanted with a responsive neurostimulation device (RNS System), involving hippocampal and ipsilateral temporal neocortical leads, and subsequently received ANT DBS. Over 1.5years, RNS System electrocorticography enabled multiscale characterization of neurophysiological effects of thalamic stimulation. In brain regions sampled by the RNS System, ANT DBS produced acute, phasic, frequency-dependent responses, including suppression of hippocampal low frequency local field potentials. ANT DBS modulated functional connectivity between hippocampus and neocortex. Finally, ANT DBS progressively suppressed hippocampal epileptiform activity in relation to the extent of hippocampal theta suppression, which informs stimulation parameter selection for ANT DBS. Taken together, this unique clinical scenario, involving hippocampal recordings of unprecedented chronicity alongside ANT DBS, sheds light on the therapeutic mechanism of thalamic stimulation and highlights capabilities needed in next-generation devices.

Stimulation of Posterior Thalamic Nuclei Induces Photophobic Behavior in Mice.

A hallmark of migraine is photophobia. In mice, photophobia-like behavior is induced by calcitonin gene-related peptide (CGRP), a neuropeptide known to be a key player in migraine. In this study, we sought to identify sites within the brain from which CGRP could induce photophobia. We focused on the posterior thalamic region, which contains neurons responsive to both light and dural stimulation and has CGRP binding sites. We probed this area with both optogenetic stimulation and acute CGRP injections in wild-type mice. Since the light/dark assay has historically been used to investigate anxiety-like responses in animals, we measured anxiety in a light-independent open field assay and asked if stimulation of a brain region, the periaqueductal gray, that induces anxiety would yield similar results to posterior thalamic stimulation. The hippocampus was used as an anatomical control to ensure that light-aversive behaviors could not be induced by the stimulation of any brain region. Optogenetic activation of neuronal cell bodies in the posterior thalamic nuclei elicited light aversion in both bright and dim light without an anxiety-like response in an open field assay. Injection of CGRP into the posterior thalamic region triggered similar light-aversive behavior without anxiety. In contrast to the posterior thalamic nuclei, optogenetic stimulation of dorsalperiaqueductal graycell bodies caused both light aversion and an anxiety-like response, while CGRP injection had no effect. In the dorsal hippocampus, neither optical stimulation nor CGRP injection affected light aversion or open field behaviors. Stimulation of posterior thalamic nuclei is able to initiate light-aversive signals in mice that may be modulated by CGRP to cause photophobia in migraine.

High-frequency electrical stimulation of the anterior thalamic nuclei increases vigilance in epilepsy patients during relaxed and drowsy wakefulness.

High-frequency deep brain stimulation (DBS) of anterior thalamic nuclei (ANT) reduces the frequency and intensity of focal and focal to bilateral tonic-clonic epileptic seizures. We investigated the impact of high-frequency ANT-DBS on vigilance in epilepsy patients during relaxed and drowsy wakefulness, to better understand the effects and the mechanisms of action of this intervention in humans. Four patients with different structural epileptic pathologies were included in this retrospective case-cohort study. Short- and long-term electroencephalography (EEG) was used to determine states of relaxed or drowsy wakefulness and the vigilance changes during stimulation-on and stimulation-off intervals. In relaxed, wakeful patients with eyes closed, the eyelid artifact rate increased acutely and reproducibly during stimulation-on intervals, suggesting an enhanced vigilance. This effect was accompanied by a slight acceleration of the alpha rhythm. In drowsy patients with eyes closed, stimulation generated acutely and reproducibly alpha rhythms, similar to the paradoxical alpha activation during eyes opening. The occurrence of the alpha rhythms reflected an increase in the vigilance of the drowsy subjects during ANT-DBS. This is the first demonstration that ANT-DBS increases the vigilance of wakeful epilepsy patients. Our results deliver circumstantial evidence that high-frequency ANT-DBS activates thalamocortical connections that promote wakefulness.

Central Lateral Thalamic Nucleus Stimulation Awakens Cortex via Modulation of Cross-Regional, Laminar-Specific Activity during General Anesthesia

Experiments identify cortical layer specific effects during induced arousal from general anesthesia. In this issue of Neuron, Redinbaugh etal. (2020) find evidence that central lateral thalamic nucleus electrical stimulation reactivates the cortex by restoring deep-layer firing rates and modulating feedforward and feedback connectivity.

Pediatric Movement Disorders and Neuromodulation: An Overview.

Pediatric movement disorders are heterogeneous and complex disorders with various aetiologies. These are broadly classified as hypo and hyperkinetic disorders. Genetic causes of basal ganglia dysfunction or direct injuries to the basal ganglia mark the genesis of these abnormal movements. The management of pediatric movement disorders is multidisciplinary with pharmacotherapy as the first line of management along with physical therapy. Patients resistant to medications are candidates for invasive neuromodulation which is an upcoming treatment modality in pediatric movement disorders. Deep brain stimulation of basal ganglia and thalamic nuclei are associated with promising symptomatic benefit with reduction in disability and improvement in quality of life of these children. In this article, we have reviewed the management of pediatric movement disorders with emphasis on neuromodulation i.e., deep brain stimulation.

Effects of anterior thalamic nuclei stimulation on gene expression in a rat model of temporal lobe epilepsy.

Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) has been shown to be effective and safe in the long-term treatment of refractory epilepsy. However, the mechanisms by which ANT-DBS controls epilepsy at the gene expression level (e.g., which regulatory mechanisms are altered) is not well understood. Nine rats were randomly assigned to the control group, the kainic acid (KA) group, and the DBS group. Temporal lobe epilepsy in rats was induced by a stereotaxic KA injection (KA group). The DBS group received the KA injection followed by treatment with ANT-DBS. Video-electroencephalogram (EEG) was used to monitor seizures. Total RNA samples were isolated from the hippocampus of three groups. Microarray was used to detect differentially regulated mRNAs. GO and pathway analysis were performed to analyze the functional categories and affected pathways. qPCR was used to prove the reliability of the microarray results. The differentially expressed genes the KA group and the DBS group, relative to the control group, were screened and a total of 2910 genes were identified. These genes were involved in functional categories such as ion channel activity (P = 5.01 × 10-8), gated channel activity (P = 1.42 × 10-7), lipid binding (P = 4.97 × 10-5), and hydrolase activity (P = 5.02 × 10-5) and pathways such as calcium signaling pathway (P = 2.09 × 10-8), glutamatergic synapse (P = 4.09 × 10-8) and NOD-like receptor signaling pathway (P = 2.70 × 10-6). Differentially expressed mRNAs might play a role in the pathogenesis of temporal lobe epilepsy. Calcium signaling pathways, synaptic glutamate, and NOD-like receptor signaling pathway play a central role in normal-epilepsy-ANT-DBS treatment series. ANT-DBS achieves its antiepileptic effects by modulating target genes involved in a variety of functions and pathways.

Deep Brain Stimulation and Drug-Resistant Epilepsy: A Review of the Literature.

Introduction: Deep brain stimulation is a safe and effective neurointerventional technique for the treatment of movement disorders. Electrical stimulation of subcortical structures may exert a control on seizure generators initiating epileptic activities. The aim of this review is to present the targets of the deep brain stimulation for the treatment of drug-resistant epilepsy.Methods: We performed a structured review of the literature from 1980 to 2018 using Medline and PubMed. Articles assessing the impact of deep brain stimulation on seizure frequency in patients with DRE were selected. Meta-analyses, randomized controlled trials, and observational studies were included.Results: To date, deep brain stimulation of various neural targets has been investigated in animal experiments and humans. This article presents the use of stimulation of the anterior and centromedian nucleus of the thalamus, hippocampus, basal ganglia, cerebellum and hypothalamus. Anterior thalamic stimulation has demonstrated efficacy and there is evidence to recommend it as the target of choice.Conclusion: Deep brain stimulation for seizures may be an option in patients with drug-resistant epilepsy. Anterior thalamic nucleus stimulation could be recommended over other targets.

Influences of anterior thalamic nucleus stimulation on neurogenesis in hippocampus of epileptic rats

Objective To investigate the influences of anterior thalamic nucleus (ANT) stimulation on neurogenesis in hippocampus of epileptic rats. Methods Thirty-two male SD rats were randomly allocated to normal-control group(n=8), control-stimulation group(n=8), sham-stimulation group(n=8) and model-stimulation group(n=8). Eqileptic SD rat model was established by using microinjection of kainic acid in hippocampal CA3 area, and administered 48 h continuous ANT stimulation in the chronic stage.Epileptic seizures were monitored and counted.The levels of Ki-67, a neurogenesis protein in hippocampus was determined by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Results The epilepsy seizure rate was (5.9±2.2) per week in the sham-stimulation group and (2.9±1.1) per week in model-stimulation group.Compared with sham-stimulated rats, ANT stimulation reduced seizures by 50.8% (P<0.05). Western blot analysis revealed that the relative levels of Ki-67 in the hippocampus of model-stimulation group significantly higher than that of the sham-stimulation group((0.44±0.15) vs (0.19±0.73), P<0.05). qRT-PCR analysis showed that relative levels of Ki-67 mRNA in the hippocampus of model-stimulation group were significantly higher than that of the sham-stimulation group((0.45±0.10) vs (0.15±0.06), P<0.05). Conclusion Chronic ANT stimulation can promote neurogenesis in epileptic rats, which may be a principle mechanism of the beneficial effect of ANT stimulation on epilepsy. Key words: Anterior thalamic nucleus; Electrical stimulation; Neurogenesis; Epilepsy

Thalamo-cortical network underlying deep brain stimulation of centromedian thalamic nuclei in intractable epilepsy: a multimodal imaging analysis.

ObjectiveDeep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) can be an alternative treatment option for intractable epilepsy patients. Since CM may be involved in widespread cortico-subcortical networks, identification of the cortical sub-networks specific to the target stimuli may provide further understanding on the underlying mechanisms of CM DBS. Several brain structures have distinguishing brain connections that may be related to the pivotal propagation and subsequent clinical effect of DBS.MethodsTo explore core structures and their connections relevant to CM DBS, we applied electroencephalogram (EEG) and diffusion tensor imaging (DTI) to 10 medically intractable patients – three generalized epilepsy (GE) and seven multifocal epilepsy (MFE) patients unsuitable for resective surgery. Spatiotemporal activation pattern was mapped from scalp EEG by delivering low-frequency stimuli (5 Hz). Structural connections between the CM and the cortical activation spots were assessed using DTI.ResultsWe confirmed an average 72% seizure reduction after CM DBS and its clinical efficiency remained consistent during the observation period (mean 21 months). EEG data revealed sequential source propagation from the anterior cingulate, followed by the frontotemporal regions bilaterally. In addition, maximal activation was found in the left cingulate gyrus and the right medial frontal cortex during the right and left CM stimulation, respectively. From DTI data, we confirmed concrete structural connections between CM and those maximal activation spots identified from EEG data.ConclusionThese results suggest that the anterior cingulate can be a core cortical structure for the bilateral propagation of CM stimulation. Our DTI findings also indicate that the propagation of CM stimulation may rely upon integrity of structural connections between CM and these key cortical regions. Structures and their connections found in this study may be relevant in the interpretation of the clinical outcomes of CM DBS.

FV 7 High-frequency anterior thalamus stimulation increases alertness in epilepsy patients during alert- and drowsy-wakefulness

Objective Deep brain stimulation (DBS) of anterior thalamic nuclei (ANT) reduces frequency and intensity of epileptic partial and secondarily-generalized seizures. ANT-DBS disrupts sleep in epilepsy patients. We investigated the impact of ANT-DBS on alertness in wakeful epilepsy patients. This might help to better understand mechanisms of action of high frequency ANT-DBS in humans. Methods Four patients with different structural epileptic pathology were included in this retrospective case-cohort study. We analysed physiological parameters of alertness during stimulation-ON and -OFF intervals in short- and long-term electroencephalograms (EEG) of patients in states of alert- and drowsy-wakefulness. Results We demonstrate that ANT-DBS increases acutely and reproducible the alertness of wakeful patients during stimulation-ON intervals. Significance This is the first demonstration of such an effect in humans. The enhanced alertness might contribute to the antiepileptic effect of ANT-DBS. Corroborated with the sleep-disruption effect of ANT-DBS in epilepsy patients, our results deliver circumstantial evidences that high-frequency ANT-DBS activates thalamo-cortical connections that promote wakefulness. In addition, our data suggest that ANT-DBS might improve the post-ictal recovery of epileptic patients and counterbalance the antiepileptic-drug induced fatigue.

EP 31. Deep brain stimulation-induced neurogenesis is gender-independent

Background Deep brain stimulation (DBS) provides substantial clinical benefits for a variety of movement disorders and lately emerged as a potential treatment for cognitive and mood disorders. Regulation of adult hippocampal neurogenesis may play a chief role in mediating DBS effects. Nevertheless, there exist significant sex differences in the regulation of neurogenesis influenced mainly by gonadal hormone exposure. Objective To investigate the hippocampal neurogenic differences between male and female awake and unrestrained rats in response to unilateral anteromedial thalamic nucleus (AMN) stimulation. Methods Four groups of adult Sprague-Dawley male and female rats received unilateral stimulation ( n = 6 each) or sham surgery of electrode implantation with no current delivery ( n = 4 each) in the right AMN; A naive group of males and females ( n = 4 each) was also included. Rats received 4 injections (50 mg/Kg/injection) of 5′-bromo-2′-deoxyuridine (BrdU) 3 days post-surgery and were euthanized 24h later. The fractionator method was used together with confocal immunofluorescent analysis to probe for BrdU-, GFAP- and NeuN-positive cells in the dentate gyrus (DG). Results Focal neurogenesis was induced in the ipsilateral DG after AMN stimulation. Stimulation-induced effects were gender-independent and translated into a 76% increase in proliferation of neural stem/progenitor cells. Conclusions Despite the difference in basal neurogenic level between male and female rats, the current study demonstrates that DBS elicits gender-independent neurogenic effects that might have implications in the treatment of cognitive and behavioral disorders irrespective of sex of patients.

Anterior thalamic stimulation for intractable epilepsy

As per W.H.O. 50 million patients are suffering from epilepsy and out of them 80% are in developing countries. In India 1% of population suffer from epilepsy. 30% of these patients become refractory to medication and would require either surgery or deep brain stimulation. Deep brain stimulation is an established therapy for Parkinson disease, essential tremor and certain form of Dystonia. Recently it has been used in intractable epilepsy with good outcome in a SANTE clinical trial. The electrical stimulation of anterior thalamus can significantly reduce the number of seizures and can improve the quality of life. Based on both animal studies and clinical trials, we subjected six patients to anterior thalamic stimulation for medically refractory epilepsy. All six selected patients were not suitable for epilepsy surgery. The age ranged from 20 years to 53 years. Bilateral anterior thalamic stimulation was done in all cases using ZD stereotactic frame under general anaesthesia. The target was calculated using fused images of CT Scan and MRI. The placement of electrodes was confirmed by microelectrode recording (thalamic burst) and intra-operative driving response obtained by scalp EEG. The post-operative CT scan was done to confirm the position of electrodes.In three patients Medtronic DBS system (Activa PC) was used while other three patients have St Jute device (Libra) device. Anticonvulsant medications were kept unchanged. The programming was started after one week using electro encephalography. The reduction or abolition of inter-ectal discharges and eeg desynchronization was kept as goal of programming. All the patients were follow-up 6 months to 4 years. Significant seizure reduction observed immediately after programming. Two patients became seizure free. Three patients have 60–80% seizure control. One patient did not get significant benefit. In three patients (good respondent) after a period of two years seizure frequency increased following battery depletion that required replacement using respectable rechargeable DBS system. Above study shows effectiveness of anterior thalamic stimulation for intractable epilepsy. Better result can only be achieved by effective eeg guided programming. Prolonged follow-up with more number of cases is required to establish deep brain stimulation of anterior thalamic nuclei as safe and effective therapy for refractory epilepsy patients who are otherwise not suitable candidate for conventional epilepsy surgery.

Neuroprotective effect of anterior thalamic nuclei stimulation on hippocampal neurons in epileptic monkeys

Objective To investigate the neuroprotective effects of anterior thalamic nuclei(ANT)stimulation on hippocampal neurons in epileptic monkeys. Methods Eight male rhesus monkeys were randomly assigned to a model control group, a sham-stimulation group, and a stimulation group. A monkey model of temporal lobe epilepsy was induced by injection of kainic acid in the left hippocampus. The seizure frequency was compared in each group. At 6 months after modeling, immunohistochemical method was used to observe the pathological injury and fibrosis in hippocampal tissue. Western blot was used to quantitatively analyze the contents of heat shock protein-70(HSP-70), NeuN, and caspase-3 in hippocampal tissue. Results All animals that received the kainic acid injections had seizures. The total number of seizures in the stimulation group was 11.2±2.3 times, compared with 21.0±4.8 times in the sham-stimulation group, it decreased 42.8%(P 0.05). The content of NeuN in sham-stimulation group was significantly lower than that in the control group and the stimulation group(P<0.01, P<0.05). The content of Caspase-3 in sham-stimulation group was significantly higher than that in the control group and the stimulation group(P<0.01, P<0.05). Conclusions Long-term ANT stimulation may reduce the hippocampal injury and gliosis in temporal lobe epilepsy monkeys. This may be an important mechanism of ANT stimulation for the treatment of temporal lobe epilepsy. Key words: Epilepsy, temporal lobe; Anterior thalamic nuclei; Deep brain stimulation; Hippocampus; Rhesus monkeys

Stimulation of Anterior Thalamic Nuclei Protects Against Seizures and Neuronal Apoptosis in Hippocampal CA3 Region of Kainic Acid-induced Epileptic Rats.

Background:The antiepileptic effect of the anterior thalamic nuclei (ANT) stimulation has been demonstrated; however, its underlying mechanism remains unclear. The aim of this study was to investigate the effect of chronic ANT stimulation on hippocampal neuron loss and apoptosis.Methods:Sixty-four rats were divided into four groups: The control group, the kainic acid (KA) group, the sham-deep brain stimulation (DBS) group, and the DBS group. KA was used to induce epilepsy. Seizure count and latency to the first spontaneous seizures were calculated. Nissl staining was used to analyze hippocampal neuronal loss. Polymerase chain reaction and Western blotting were conducted to assess the expression of caspase-3 (Casp3), B-cell lymphoma-2 (Bcl2), and Bcl2-associated X protein (Bax) in the hippocampal CA3 region. One-way analysis of variance was used to determine the differences between the four groups.Results:The latency to the first spontaneous seizures in the DBS group was significantly longer than that in the KA group (27.50 ± 8.05 vs. 16.38 ± 7.25 days, P = 0.0005). The total seizure number in the DBS group was also significantly reduced (DBS vs. KA group: 11.75 ± 6.80 vs. 23.25 ± 7.72, P = 0.0002). Chronic ANT-DBS reduced neuronal loss in the hippocampal CA3 region (DBS vs. KA group: 23.58 ± 6.34 vs. 13.13 ± 4.00, P = 0.0012). After chronic DBS, the relative mRNA expression level of Casp3 was decreased (DBS vs. KA group: 1.18 ± 0.37 vs. 2.09 ± 0.46, P = 0.0003), and the relative mRNA expression level of Bcl2 was increased (DBS vs. KA group: 0.92 ± 0.21 vs. 0.48 ± 0.16, P = 0.0004). The protein expression levels of CASP3 (DBS vs. KA group: 1.25 ± 0.26 vs. 2.49 ± 0.38, P < 0.0001) and BAX (DBS vs. KA group: 1.57 ± 0.49 vs. 2.80 ± 0.63, P = 0.0012) both declined in the DBS group whereas the protein expression level of BCL2 (DBS vs. KA group: 0.78 ± 0.32 vs. 0.36 ± 0.17, P = 0.0086) increased in the DBS group.Conclusions:This study demonstrated that chronic ANT stimulation could exert a neuroprotective effect on hippocampal neurons. This neuroprotective effect is likely to be mediated by the inhibition of apoptosis in the epileptic hippocampus.