Motor Cortex Stimulation for Post-Stroke Thalamic Pain

Overview

The goal of this clinical trial is to investigate the mechanisms and predictive factors of motor cortex stimulation (MCS) for treating post-stroke thalamic pain, a challenging central neuropathic pain condition. Approximately 25% of patients show no short-term response to MCS, and about 20% experience long-term efficacy decay, yet the underlying analgesic mechanisms remain unclear and objective predictive biomarkers are lacking. This study aims to answer the following main questions: How does MCS modulate thalamic pain through the coordinated interaction of structural connectivity, functional network dynamics, and metabolic balance in the brain? What are the distinct neuroimaging characteristics that differentiate short-term non-responders, long-term responders, and those with long-term efficacy decay? Which multimodal imaging biomarkers can reliably predict short-term and long-term MCS efficacy? Participants will undergo a two-stage MCS surgical procedure. In stage I, epidural electrodes are implanted over the motor cortex, followed by a 2-week external trial stimulation. Participants who achieve a ≥50% reduction in Visual Analog Scale (VAS) pain score will proceed to stage II, receiving an implanted pulse generator for long-term stimulation. Those who do not respond in the short term will have the electrodes removed without undergoing stage II implantation. All participants will complete baseline clinical assessments and multimodal MRI scans (including T1, DTI, resting-state fMRI, and MRS) before surgery. Participants who receive the permanent implant will undergo follow-up clinical evaluations and repeat MRI scans at 3 and 6 months post-surgery. Researchers will compare imaging features across three outcome groups-short-term non-responders, long-term responders, and long-term decay group-to identify predictive biomarkers. Multimodal imaging data will be integrated using LASSO regression to build prediction models for both short-term screening and long-term efficacy warning. This research is expected to establish a "mechanism exploration - efficacy prediction - clinical decision" paradigm, providing objective imaging-based evidence to guide patient selection and postoperative management for MCS treatment.

Background and Rationale Post-stroke thalamic pain is a refractory central neuropathic pain condition that significantly impairs patients' quality of life. Motor cortex stimulation (MCS) has emerged as a promising neuromodulatory therapy, yet its clinical application faces two major challenges: approximately 25% of patients show inadequate short-term response during the external trial phase, and about 20% of initial responders experience progressive efficacy decay within six months of permanent implantation. The neural mechanisms underlying MCS analgesia remain incompletely understood, and objective predictors for patient selection and long-term outcome are lacking. Study Design This is a prospective, single-arm cohort study conducted at Aerospace Center Hospital, Beijing, China. A total of 200 patients with refractory post-stroke thalamic pain will be enrolled. All participants will undergo a standardized two-stage MCS surgical protocol. The study design incorporates comprehensive clinical assessments and multimodal MRI acquisition at baseline, with longitudinal follow-up at 3 and 6 months post-surgery for patients receiving permanent implants. Surgical Protocol The study employs a modified MCS surgical technique. Preoperative planning utilizes multimodal imaging-guided navigation combined with individual functional brain mapping to identify the optimal motor cortex coverage area. Two 8-contact epidural paddle electrodes are implanted in parallel over the primary motor cortex (M1) and adjacent premotor areas through a small craniotomy. Intraoperative electrophysiological monitoring, including somatosensory evoked potentials (SEP) for central sulcus localization and motor evoked potentials (MEP) for motor area verification, guides precise electrode placement. The procedure is conducted in two stages. Stage I involves electrode implantation and external trial stimulation. Following a 2-week trial period with programmed stimulation parameters (40 Hz, 200 μs pulse width), short-term response is determined based on a ≥50% reduction in Visual Analog Scale (VAS) score from baseline. Responders proceed to Stage II for implantation of an internal pulse generator, while non-responders undergo electrode removal without permanent implantation. Multimodal Imaging Protocol All participants undergo a comprehensive MRI protocol at baseline (approximately 38 minutes per session), including: High-resolution 3D T1-weighted imaging for structural segmentation and thalamic volumetric analysis Diffusion tensor imaging (DTI) with 64 diffusion directions for white matter tractography and pathway integrity assessment Resting-state functional MRI (rs-fMRI) for functional connectivity analysis Magnetic resonance spectroscopy (MRS) targeting bilateral thalamus, anterior cingulate cortex, and insula for quantification of glutamate, GABA, NAA, choline, and creatine concentrations Participants receiving permanent implants undergo repeat MRI scans at 3 and 6 months post-surgery to capture longitudinal changes in structural, functional, and metabolic measures. Clinical Assessments Clinical evaluations are conducted at baseline, 2 weeks (end of trial period), and 3 and 6 months post-surgery. Assessments include: Pain measures: Visual Analog Scale (VAS), Short-Form McGill Pain Questionnaire (SF-MPQ), Pain Catastrophizing Scale (PCS) Quality of life and function: SF-36, Pittsburgh Sleep Quality Index (PSQI), Patient Global Impression of Change (PGIC) Emotional and cognitive function: Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Montreal Cognitive Assessment (MoCA) Adverse event and complication monitoring Analytical Framework The study employs a "structure-function-metabolism" three-dimensional analytical framework to investigate MCS mechanisms: Structural dimension: Corticothalamic pathway integrity assessed by DTI metrics (FA, MD, RD) and thalamic gray matter volume Functional dimension: Default mode network (DMN) and salience network (SN) connectivity dynamics derived from rs-fMRI independent component analysis Metabolic dimension: Glutamate/GABA ratio and other metabolite concentrations in pain-related brain regions Outcome Classification Participants are categorized into three outcome groups based on their clinical trajectory: Short-term non-responders: VAS improvement \<50% at 2-week trial (no Stage II implantation) Long-term responders: VAS improvement ≥50% at both 2-week trial and 6-month follow-up Long-term decay group: VAS improvement ≥50% at 2-week trial but \<50% at 6-month follow-up Predictive Modeling The study aims to develop two predictive models: Short-term screening model: Identifying baseline imaging biomarkers that distinguish short-term responders from non-responders, using LASSO-penalized logistic regression with cross-validation Long-term warning model: Among short-term responders, identifying baseline "vulnerability" markers and neuroplasticity indicators associated with 6-month efficacy decay Sample Size and Statistical Plan Based on preliminary data from 50 prior cases, the expected outcome distribution is: 25% short-term non-responders, 60% long-term responders, and 15% long-term decay. With a target enrollment of 200 participants, the study is adequately powered for group comparisons and predictive factor identification. Statistical analyses include Kruskal-Wallis H test for three-group comparisons, LASSO regression for feature selection, and area under the curve (AUC) for model performance evaluation. Longitudinal changes within groups will be analyzed using paired t-tests or Wilcoxon signed-rank tests. Multiple comparisons will be corrected using false discovery rate (FDR). Sensitivity analyses will be performed using alternative VAS thresholds (≥30%, ≥70%) and bootstrap resampling. Expected Impact This research is expected to elucidate the neurobiological mechanisms of MCS analgesia through structural-functional-metabolic integration, identify reliable imaging biomarkers for patient selection, and establish a clinical decision-support framework for personalized MCS therapy in post-stroke thalamic pain.