Motor Cortex Stimulation for Post-Stroke Thalamic Pain

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.