Ying-Chuan Chen

Potential Protective Effects of Chronic Anterior Thalamic Nucleus Stimulation on Hippocampal Neurons in Epileptic Monkeys

BACKGROUND Stimulation of the anterior nucleus of the thalamus (ANT) is effective in seizure reduction, but the mechanisms underlying the beneficial effects of ANT stimulation are unclear. OBJECTIVE To assess the beneficial effects of ANT stimulation on hippocampal neurons of epileptic monkeys. METHODS Chronic ANT stimulation was applied to kainic acid-induced epileptic monkeys. Behavioral seizures were continuously monitored. Immunohistochemical staining and western blot assays were performed to assess the hippocampal injury and the effects of ANT stimulation. RESULTS The frequency of seizures was 42.8% lower in the stimulation group compared with the sham-stimulation group. Immunohistochemical staining and western blot analyses indicated that neuronal loss and apoptosis were less severe and that neurofilament synthesis was enhanced in the stimulation monkeys compared with the sham-stimulation group. These data showed that the hippocampal injury was less severe in monkeys in the stimulation group than in those in the sham-stimulation group. CONCLUSIONS Our data suggest that chronic ANT stimulation may exert protective effects on hippocampal neurons and boost the regeneration of neuronal fibers. These effects may be closely related to the mechanisms of ANT stimulation in epilepsy treatment.

Deep brain stimulation of the anterior nucleus of the thalamus reverses the gene expression of cytokines and their receptors as well as neuronal degeneration in epileptic rats.

BACKGROUND Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is effective in seizure control. However, the mechanisms remain unclear. METHODS Sixty-four rats were randomly assigned to the control group, the kainic acid (KA) group, the sham-DBS group and the DBS group. Video-electroencephalogram (EEG) was used to monitor seizures. Quantitative real time PCR (qPCR) was applied for detecting interleukin-1 beta (IL-1β), IL-1 receptor (IL-1R), IL-6, IL-6 receptor (IL-6R), gp130, tumor necrosis factor-alpha (TNF-α), TNF-receptor 1 (TNF-R1) and TNF-receptor 2 (TNF-R2) expression 12h after the establishment of an epileptic model. The neuronal structural degeneration in the hippocampus was evaluated with transmission electron microscopy (TEM) at this same time point. RESULTS The seizure frequency was 48.6% lower in the DBS group compared with the sham-DBS group (P<0.01). The expression of IL-1β, IL-1R, IL-6, IL-6R, gp130, TNF-α and TNF-R1 was elevated in both the KA and the sham group compared with the control group (all Ps<0.01). Additionally, ANT-DBS was able to reverse this gene expression pattern in the DBS group compared with the sham-DBS group (all Ps<0.01). There was no significant difference in TNF-R2 expression among the four groups. The neuronal structural degeneration in the KA group and the sham-DBS group was more severe than that in the control group (injury scores, all Ps<0.01). ANT-DBS was also capable of relieving the degeneration compared with the sham-DBS group (injury score, P<0.01). CONCLUSIONS This study demonstrated that ANT-DBS can reduce seizure frequency in the early stage in epileptic rats as well as relieve the pro-inflammatory state and neuronal injury, which may be one of the most effective mechanisms of ANT-DBS against epileptogenesis.

Effects of anterior thalamic nuclei deep brain stimulation on neurogenesis in epileptic and healthy rats

BACKGROUND The efficacy of anterior thalamic nuclei (ANT) deep brain stimulation (DBS) in mitigating epileptic seizures has been established. Though the neuroprotection of ANT-DBS has been illustrated, the seizure mitigating mechanism of ANT-DBS has not been thoroughly elucidated. In particular, the effect of ANT-DBS on neurogenesis has not been reported previously. METHOD Thirty-two male Sprague Dawley rats were randomly assigned to the following groups: sham-DBS-healthy (HL) (n=8), DBS-HL (n=8), sham-DBS-epilepsy (EP) (n=8) and DBS-EP (n=8). Normal saline and kainic acid were injected, respectively, into the former and later two groups, and seizures were monitored. One month later, rats received electrode implantation. Stimulation was exerted in the DBS group but not in the sham-DBS group. Next, all rats were sacrificed, and the ipsilateral hippocampus was dissected and prepared for quantitative real time PCR (qPCR) and western blot analysis in order to measure neuronal nuclear (NeuN), brain-derived neurotrophic factor (BDNF), doublecortin (DCX) and Ki-67 expressions. RESULTS A 44.4% seizure frequency reduction was obtained after ANT-DBS, and no seizures was observed in healthy rats. NeuN, BDNF, Ki-67 and DCX expression levels were significantly decreased in the epileptic rats compared to healthy rats (P<0.01 or P<0.05). Obvious increases in NeuN, Ki-67 and DCX expressions were observed in epileptic and healthy rats receiving stimulation compared to rats receiving no stimulation (all Ps<0.01). However, BDNF expression was not affected by ANT-DBS (all Ps>0.05). CONCLUSIONS (1) ANT-DBS reduces neuronal loss during the chronic stage of epilepsy. (2) Neurogenesis is elevated by ANT-DBS in both epileptic and healthy rats, and this elevation may not be regulated via a BDNF pathway.

Subthalamic nucleus deep brain stimulation protects neurons by activating autophagy via PP2A inactivation in a rat model of Parkinson's disease

ABSTRACT Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for alleviating disability in patients with moderate to severe Parkinsons disease (PD). Preclinical studies have shown that stimulation of the rat STN can protect against nigral dopaminergic neuron loss. However, the underlying mechanism is unclear. To investigate the molecular basis of the neuroprotective effects of STN stimulation, a rat model of PD was established by unilaterally injecting 6‐hydroxydopamine (6‐OHDA) into the striatum. PD rats were subjected to DBS of the STN (STN‐DBS) and the effects on motor symptoms and number of nigral tyrosine hydroxylase‐positive (TH+) neurons was examined. We found that STN‐DBS improved movement disorder and mitigated the loss of TH+ neurons induced by 6‐OHDA. Furthermore, STN‐DBS blocked protein phosphatase (PP)2A activation induced by 6‐OHDA and led to the phosphorylation of B cell lymphoma (Bcl)‐2, thereby increasing its activity. This induced its disassociation from Beclin1, a positive regulator of autophagy, leading to autophagy and inhibition of apoptosis. These findings demonstrate for the first time that STN‐DBS could exert neuroprotective effects against 6‐OHDA‐induced cell injury in PD by inducing autophagy via PP2A inactivation and dissociation of the Bcl‐2/Beclin1 complex, thereby providing a molecular basis of STN‐DBS neuroprotection for PD. HIGHLIGHTSSTN‐DBS protects dopaminergic neurons against 6‐OHDA‐induced cell death.STN‐DBS could exert neuroprotective effects by inducing autophagy.STN‐DBS may activate autophagy by negatively regulating PP2A activity.

Delayed responses of subthalamic nucleus to deep brain stimulation in patients with Parkinson's disease

Cases 6 3 Male/Female 1(16.7%)/5(83.3%) 1(33.3%)/2(66.7%) Age 66.3 ± 4.4 years 69.0 ± 6.6 years Disease History 8.5 ± 3.3 years 8.7 ± 2.5 years Daily Madopar Dose 0.75e2.25 pills 1.50e3.00 pills Bilateral/Unilateral Symptom 4(66.7%)/2(33.3%) 3(100%)/0(0) Preoperative UPDRS-III score 36.8 ± 6.9 41.3 ± 7.6 Target posterior to RN 0.7 ± 0.4 mm 0.9 ± 0.5 mm STN MER length 7.5 ± 1.2 mm 5.1 ± 1.0 mm Bilateral/Unilateral Delayed Responses 2(33.3%)/4(66.7%) 3(100%)/0(0) UPDRS-III score 1 year after surgery 23.5 ± 7.7 # 27.0 ± 7.0 #

Anterior thalamic nuclei deep brain stimulation reduces disruption of the blood–brain barrier, albumin extravasation, inflammation and apoptosis in kainic acid-induced epileptic rats

Abstract Objective The therapeutic efficacy of anterior thalamic nuclei deep brain stimulation (ATN-DBS) against seizures has been largely accepted; however, the effects of ATN-DBS on disruption of the blood–brain barrier (BBB), albumin extravasation, inflammation and apoptosis still remain unclear. Methods Rats were distributed into four treatment groups: physiological saline (PS, N = 12), kainic acid (KA, N = 12), KA-sham-DBS (N = 12) and KA-DBS (N = 12). Seizures were monitored using video-electroencephalogram (EEG). One day after surgery, all rats were sacrificed. Then, samples were prepared for quantitative real-time PCR (qPCR), western blot, immunofluorescence (IF) staining, and transmission electron microscopy to evaluate the disruption of the BBB, albumin extravasation, inflammation, and apoptosis. Result Because of the KA injection, the disruption of the BBB, albumin extravasation, inflammation and apoptosis were more severe in the KA and the KA-sham-DBS groups compared to the PS group (all Ps < 0.05 or < 0.01). The ideal outcomes were observed in the KA-DBS group. ATN-DBS produced a 46.3% reduction in seizure frequency and alleviated the disruption of the BBB, albumin extravasation, inflammatory reaction and apoptosis in comparison to the KA-sham-DBS group (all Ps < 0.05 or < 0.01). Conclusion (1) Seizures can be reduced using ATN-DBS in the epileptogenic stage. (2) ATN-DBS can reduce the disruption of the BBB and albumin extravasation. (3) ATN-DBS has an anti-inflammatory effect in epileptic models.

Ultrahigh-Magnitude Brain Magnetic Resonance Imaging Scan on Rhesus Monkeys With Implanted Deep Brain Stimulation Hardware: ULTRAHIGH MRI ON MONKEYS WITH DBS HARDWARE

Patients with implanted deep brain stimulation (DBS) hardware are prohibited from undergoing magnetic resonance imaging (MRI) scans at magnitudes greater than 1.5 T to avoid potential MRI‐related heating injury. Whether DBS devices are compatible with higher field MRI scanning is unknown. This study aimed to investigate whether 7.0 T and 3.0 T MRI scans can be safely performed on rhesus monkeys with implanted DBS devices.

Anterior nucleus of thalamus stimulation inhibited abnormal mossy fiber sprouting in kainic acid-induced epileptic rats

BACKGROUND Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) has demonstrated antiepileptic efficacy, especially for mesial temporal lobe epilepsy (MTLE). Mossy fiber sprouting (MFS) is involved in the pathogenesis of MTLE, and Sema-3A and GAP-43 are pivotal regulators of MFS. This study investigated the effects of ANT-DBS on MFS and expression levels of Sema-3A and GAP-43 as a possible mechanism for seizure suppression. METHODS Adult male Sprague-Dawley rats were randomly divided into four groups: (1) control (saline injection), (2) KA (kainic acid injection), (3) KA + Sham-DBS (electrode implantation without stimulation), and (4) KA + DBS (electrode implantation with stimulation). Video electroencephalography (EEG) was used to ensure model establishment and monitor seizure frequency, latency, and severity (Racine stage). Chronic ANT stimulation was conducted for 35 days in the KA + DBS group, and MFS compared to the other groups by quantitative Timm staining. Sema-3A and GAP-43 expression levels in the hippocampal formation were evaluated in all groups with western blot. RESULTS The latency period was significantly prolonged and spontaneous seizure frequency reduced in the KA + DBS group compared to KA and KA + Sham-DBS groups. Staining scores for MFS in CA3 and dentate gyrus (DG) were significantly lower in the KA + DBS group. The KA + DBS group also exhibited decreased GAP-43 expression and increased Sema-3A expression compared to KA and KA + Sham-DBS groups. CONCLUSION These results suggest that ANT-DBS extends the latent period following epileptogenic stimulation by impeding MFS through modulation of GAP-43 and Sema-3A expression.

Doesn't subthalamic nucleus deep brain stimulation have a neuroprotective effect in Parkinson's disease patients?

Recently, we enthusiastically read the paper by Lilleeng B et al. titled “Progression and survival in Parkinson’s disease with subthalamic nucleus stimulation” published in your journal.1 Subthalamic nucleus (STN) deep brain stimulation (DBS) is a novel neurostimulation technique used in treating Parkinson’s disease (PD).2 Despite its efficacy, the mechanisms of STNDBS remain unclear.2 The neuroprotective effect of STNDBS in patients with PD has been observed in numerous studies.3,4 However, a few studies offer a different opinion. In this paper, patients were separated into two groups (Group A included all the patients with PD who received STNDBS from January 2001 to December 2007 at Oslo University Hospital; Group B included the patients with PD from a prevalence study in the Stavanger area of Western Norway in 1993). No significant difference (longterm mortality and annual change in the Unified Parkinson’s Disease Rating Scale [UPDRS]III scores) was noted between the two groups. Therefore, a conclusion was drawn that STNDBS in patients with PD does not offer modifying or neuroprotective effects based on the results.1 Nevertheless, this conclusion might require further discussion given the methods involved in this study. Firstly, researchers set Group B as the “control group”. However, many antiPD medications have a neuroprotective effect and might be influenced by STNDBS. Therefore, it is likely inappropriate to evaluate the neuroprotective effect of STNDBS compared with a medicated group. Bernardino Ossola et al. found that amantadine protects dopaminergic neurons by reducing the activation of microglia and inducing glial cell linederived neurotrophic factor (GNDF) expression in astroglia.5 M. Mohanasundari et al. showed that bromocriptine can enhance neuroprotective effects in mice with PD induced by 1methyl4phenyl1,2,3,6tetrahydropyridine (MPTP).6 Via positron emission tomography (PET), Whone AL et al. discovered a slower progression of PD with ropinirole vs levodopa in patients with PD.7 Additionally, pramipexole was observed less development of motor complications in a doubleblind trail, indicating neuroprotection by pramipexole.8 Another study arrived at a similar conclusion via singlephoton emission computed tomography (SPECT) imaging.9 In addition, rotigotine exhibited a neuroprotective effect in MPTPinduced PD monkeys.10 Furthermore, the effect on neuroprotection may not simply be additive given that an interaction may exist between STNDBS and medication. Therefore, denying that STNDBS affects neuroprotection according to a comparison with the medicated group could be controversial because the patients in the medicated group were influenced by neuroprotective effects. Secondly, the researchers performed a second matching of the two groups based primarily on age.1 A recent metaanalysis found that increasing age and dementia are closely associated with the mortality of patients with PD.11 Hence, it is possibly better to conduct the second matching based on both age and dementia. Furthermore, the baseline data of the STNDBS group were obtained 3 months after the initiation of STNDBS. In our experience, the motor symptoms of patients with PD undergoing STNDBS are more stable and the medicine dosage could be reduced 6 months after DBS initiation. Additionally, numerous DBSrelated studies evaluated symptoms after this time point.12 The change in UPDRSIII scores could be influenced by the time point of the test. Thirdly, in group A, the UPDRSIII score was evaluated in the medication and stimulation “on” state.1 Given that the antiPD medicine type and dose changes based on the disease process, which may affect the UPDRSIII measurement, evaluation in an “off” stimulation and “off” medication state would be better. This method has been used in many studies.13 Fourthly, unlike animal experiments, clinical studies are restricted by many factors. In

Could cough be an intraoperative indicator for venous air embolism in deep brain stimulation surgeries?: experiences from a large case series

BackgroundDeep brain stimulation (DBS) surgery is usually performed with the patients located in a half-sitting position. Therefore, complications associated with such position accompany, such as venous air embolism (VAE), et al. However, because the patients are fully conscious during the surgery, they may have observable manifestations related to the complications that are otherwise inconspicuous in generally anesthetic surgeries. Thus, we designed this study to investigate the intraoperative manifestations of the potentially dangerous complication of VAE in the DBS surgery.MethodsThe medical records of a series of 705 consecutive patients who underwent DBS surgery in our hospital have been retrospectively reviewed. The clinical features, intraoperative manifestations and treatment of these patients were analyzed for evidence of VAE. The correlation between the cough intensity and other clinical features were investigated.ResultsEvidence of VAE were found in 16 patients. Statistical analyses showed that severe cough is associated with greater age (p = 0.045), longer coughing time (p = 0.001), more intensive tremor (p = 0.032), more complaints (p = 0.036), greater influences (p = 0.009), more treatment (p = 0.003) and longer hospitalization (p = 0.003).ConclusionsIntraoperative intense and unremitting cough may be a noticeable indicator of possible VAE. Early recognition and effective management are essential to prevent unfavorable outcomes in such cases.