"Stroke is a leading cause of death and disability in industrialized countries. Central post-stroke pain (CPSP) refers to pain that results from a primary lesion or dysfunction of the central nervous system after a stroke. Because of potential under-diagnosis, difficulty managing the condition, and studies that have been unable to clearly establish the detailed mechanisms of CPSP, diagnostic and therapeutic strategies for CPSP are limited. There are two urgent issues, diagnosis and treatment, that are encountered when facing CPSP. There are currently no standardized accepted diagnostic criteria, clear definitions or simple diagnostic tests that enable us to accurately distinguish between pain types. Developing more objective approaches to providing a clear diagnosis is essential. Current treatments for CPSP involve pharmacological approaches that are not very effective in achieving a satisfactory therapeutic response. Non-invasive brain stimulation, such as tDCS, has been developed for this purpose. Based on our findings of the involvement of P2X receptors, BDNF, and cytokines in CPSP and abnormal neuronal hyperexcitability, our first hypothesis is that these factors are valuable predictive elements for the occurrence of central pain conditions. Current efforts in developing treatments for CPSP have focused on regulating the sensitized thalamocortical pathway. To achieve specific and efficient effects on the regulation of hyperexcitable neurons, we need to develop methods that specifically target these neurons and produce a suppressive effect. Our second hypothesis is that targeting the hyperexcitability of the damaged thalamocortical system is a rationale for further studies on therapeutic agents for the treatment of central pain, including the use of non-invasive brain stimulation techniques, such as tDCS. Thus, the use of pre-clinic experimental models which will contribute aids in addressing these issues serves as an important basis that hence may be translated into the clinical setting to benefit patients.
The general aim of the present proposal is to address the current difficulties in the diagnosis and treatment of CPSP. We propose two specific aims to achieve this important goal. Specific Aim I focuses on searching for a biomarker for the early detection and diagnosis of CPSP. The biomarkers include brain-derived neurotrophic factor (BDNF), P2X receptors, and cytokines and the application of analytic technique of electroencephalography (EEG). Specific Aim II focuses on developing a therapeutic strategy for the treatment of CPSP. We will investigate the neuronal mechanisms that underlie non-invasive brain stimulation techniques: transcranial direct-current stimulation (tDCS). We will develop optimal stimulation parameters for clinical application. We also propose to investigate the therapeutic effect of novel optogenetic and chemogenetic approaches to provide effective treatment options for CPSP in patients. A novel, wearable, remote feedback-controlled device will be constructed based on EEG signal detection and analysis. We will establish sophisticated animal models mimicking human neurological disorders and handle wide varieties of approaches such as molecular biology, biochemistry, behavioral assessments and neuro-pharmacological, electrophysiological methods to bring integrated dynamic links from the hemorrhagic stroke pre-clinical mouse models to human diseases. The proposed study will be multidisciplinary translational research, combining basic and clinical applications in animal disease models and clinical patient experiments."