Yixin Pan

Subthalamus deep brain stimulation for primary dystonia patients: a long-term follow-up study.

Deep brain stimulation has generated sustained improvement in motor function for patients with dystonia, but the long‐term impact of subthalamic nucleus stimulation on dystonia has not been elucidated.

Over-expression of tetraspanin 8 in malignant glioma regulates tumor cell progression.

Tumor cell invasion and proliferation remain the overwhelming causes of death for malignant glioma patients. To establish effective therapeutic methods, new targets implied in these processes have to be identified. Tetraspanin 8 (Tspn8) forms complexes with a large variety of trans-membrane and/or cytosolic proteins to regulate several important cellular functions. In the current study, we found that Tspn8 was over-expressed in multiple clinical malignant glioma tissues, and its expression level correlated with the grade of tumors. Tspn8 expression in malignant glioma cells (U251MG and U87MG lines) is important for cell proliferation and migration. siRNA-mediated knockdown of Tspn8 markedly reduced in vitro proliferation and migration of U251MG and U87MG cells. Meanwhile, Tspn8 silencing also increased the sensitivity of temozolomide (TMZ), and significantly increased U251MG or U87MG cell death and apoptosis by TMZ were achieved with Tspn8 knockdown. We observed that Tspn8 formed a complex with activated focal adhesion kinase (FAK) in both human malignant glioma tissues and in above glioma cells. This complexation appeared required for FAK activation, since Tspn8 knockdown inhibited FAK activation in U251MG and U87MG cells. These results provide evidence that Tspn8 contributes to the pathogenesis of glioblastoma probably by promoting proliferation, migration and TMZ-resistance of glioma cells. Therefore, targeting Tspn8 may provide a potential therapeutic intervention for malignant glioma.

Tetraspanin 8-Rictor-Integrin α3 Complex Is Required for Glioma Cell Migration

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in malignant gliomas. We found that Tspan8 expression level is high in both malignant glioma tissues and in several human glioma cell lines, where it formed a complex integrin α3 and rictor, the latter is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Disruption of this complex, through siRNA-mediated knockdown of anyone of these three proteins, inhibited U251MG glioma cell migration in vitro. We further showed that Tspan8-rictor association appeared required for mTORC2 activation. Knockdown of Tspan8 by the targeted siRNAs prevented mTOR-rictor (mTORC2) assembly as well as phosphorylation of AKT (Ser-473) and protein kinase C α (PKCα) in U251MG cells. Together, these results demonstrate that over-expressed Tspan8 in malignant glioma forms a complex with rictor and integrin α3 to mediate mTORC2 activation and glioma cell migration. Therefore, targeting Tspan8-rictor-integrin α3 complex may provide a potential therapeutic intervention for malignant glioma.

GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings

Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621’s cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)’s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent.

Surgical Treatments for Anorexia Nervosa

Anorexia nervosa (AN) is a severe psychiatric disorder with high rates of morbidity and mortality. An estimated 21 % of patients experience a chronic course despite treatment with the best available medications and behavioral therapies. Existing data suggest that lesioning and deep brain stimulation can benefit a large proportion (ranging from 60 to 80 %) of patients with medically intractable AN. Long-term serious adverse events are very infrequent. Functional neuroimaging studies have increased our understanding of the mechanisms of disease development and therapeutic action. At our institution, we grade AN on a four-point scale based on patient clinical characteristics and our surgical experience over the past 8 years. This scale is particularly useful for guiding the selection of surgical procedures. Such treatment options include deep brain stimulation or lesioning of the nucleus accumbens , anterior capsulotomy, and anterior cingulotomy. Data suggest that surgical treatment is a viable option for intractable AN, and can alleviate suffering and improve the quality of life of patients with these disabling disorders.

Effect of Bilateral Anterior Cingulotomy on Chronic Neuropathic Pain with Severe Depression

BACKGROUND The presence of neuropathic pain can severely impinge on emotional regulation and activities of daily living including social activities, resulting in diminished life satisfaction. Unfortunately, the majority of patients with neuropathic pain do not experience an amelioration of symptoms from conventional therapies, even when multimodal therapies are used. Chronic refractory neuropathic pain is usually accompanied by severe depression that is prone to incur suicidal events; thus clinical management of chronic neuropathic pain and depression presents a serious challenge for clinicians and patients. CASE DESCRIPTION Two patients presented at our institution with neuropathic pain and severe depression. The patients had different pain symptoms emerging a few months after central or peripheral nervous system impairment. These symptoms were associated with the development of severe depression, social isolation, and a gradual inability to perform daily activities. Both patients were referred to our treatment center for bilateral anterior cingulotomy. After surgery, both patients showed significant progressive improvements in perceived pain, mental health status, and daily functioning. CONCLUSIONS Bilateral anterior cingulotomy may serve as an alternative treatment for medically refractory neuropathic pain, especially for patients who also experience depression.

Spinal Cord Stimulation Combined with Anterior Cingulotomy to Manage Refractory Phantom Limb Pain

Background: Phantom limb pain (PLP) is an intractable and debilitating disease without satisfactory treatment options presently available. Central reorganization, peripheral changes, and psychiatric factors contribute to its development; thus, a neuropsychiatry-orientated combined therapy could be promising. Objectives: We used a combined strategy with the aims of demonstrating its therapeutic outcomes on PLP. Methods: The patient initially received spinal cord stimulation (SCS) implantation and then anterior cingulotomy (ACING) 2 years later. We administered the Hamilton Depression Scale-24, Hamilton Anxiety Scale, Pain Rating Index, Numerical Pain Rating Scale, and the Short Form (36) Health Survey to assess its outcomes at 5 time points, namely the time before performing SCS implantation, 1 year and 2 years after SCS implantation, and 1 year and 2 years after SCS combined with ACING. Results: Excellent pain relief and significant improvement in depression symptoms were observed in this patient with PLP who underwent SCS combined with ACING. Conclusions: This report suggests that SCS combined with ACING is efficacious for PLP. However, further studies are warranted.

Subthalamic deep brain stimulation in patients with primary dystonia: A ten-year follow-up study

BACKGROUND Subthalamic deep brain stimulation (STN-DBS) is a promising intervention for primary dystonia; however, evidence regarding its efficacy is lacking. Thus, a long-term follow-up is indispensable. OBJECTIVE This trial was designed to examine the efficacy and consistency of subthalamic deep brain stimulation in patients with primary dystonia over the long term. METHOD This was a retrospective study involving 14 patients with primary dystonia who underwent STN-DBS and consented to a follow-up of at least 10 years. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and 36-item Short-Form General Health Survey were employed, at five time points (pre-operation [baseline], 1 month post-operation, 1 year post-operation, 5 years post-operation, and last follow-up), to assess improvement of dystonic symptoms and changes in quality of life. OUTCOMES All patients gained extensive clinical benefits from STN-DBS therapy, without experiencing serious adverse effects. Improvements of 59.0% at 1 month, 85.0% at 1 year, and 90.8% at 5 years after the operation, and up to 91.4% at the last follow-up, were demonstrated by movement evaluation with the BFMDRS. All patients achieved a substantial improvement in quality of life. CONCLUSION Subthalamic deep brain stimulation is an effective and persisting alternative to pallidal deep brain stimulation, and importantly, it is very safe even with extremely long-term chronic stimulation.

Deep Brain Stimulation of the Internal Globus Pallidus Improves Response Initiation and Proactive Inhibition in Patients With Parkinson’s Disease

Background: Impulse control disorder is not uncommon in patients with Parkinson’s disease (PD) who are treated with dopamine replacement therapy and subthalamic deep brain stimulation (DBS). Internal globus pallidus (GPi)-DBS is increasingly used, but its role in inhibitory control has rarely been explored. In this study, we evaluated the effect of GPi-DBS on inhibitory control in PD patients. Methods: A stop-signal paradigm was used to test response initiation, proactive inhibition, and reactive inhibition. The subjects enrolled in the experiment were 27 patients with PD, of whom 13 had received only drug treatment and 14 had received bilateral GPi-DBS in addition to conventional medical treatment and 15 healthy individuals. Results: Our results revealed that with GPi-DBS on, patients with PD showed significantly faster responses than the other groups in trials where it was certain that no stop signal would be presented. Proactive inhibition was significantly different in the surgical patients with GPi-DBS on versus when GPi-DBS was off, in surgical patients with GPi-DBS on versus drug-treated patients, and in healthy controls versus drug-treated patients. Correlation analyses revealed that when GPi-DBS was on, there was a statistically significant moderate positive relationship between proactive inhibition and dopaminergic medication. Conclusion: GPi-DBS may lead to an increase in response initiation speed and improve the dysfunctional proactive inhibitory control observed in PD patients. Our results may help us to understand the role of the GPi in cortical-basal ganglia circuits.

Neurosurgery for the Treatment of Refractory Schizophrenia

Schizophrenia is a chronic, severe, and disabling psychiatric disease that is characterized by perturbations in cognition, affect, and behavior. Of the many available treatments, pharmaceutical interventions remain as first choice-treatments. However, about 20 % of patients with schizophrenia exhibit refractory schizophrenia that does not respond well to pharmaceutical treatments. As a result, neurosurgery performed for the treatment of refractory schizophrenia, also called psychosurgery, is an alternative treatment that has a long history. With the refinement and improved accuracy of neuroimaging techniques, modern psychosurgery has greater success with fewer risks. Nevertheless, these procedures are still invasive methods and the resulting lesions are irreversible. Therefore, we must keep in mind that surgical therapy should only be considered as a supplementary part of the comprehensive treatment of schizophrenia and the inclusion criteria for surgery must be strict.