Neuromodulation for Pain: A Comprehensive Survey and Systematic Review of Clinical Trials and Connectomic Analysis of Brain Targets

Abstract

<b><i>Background:</i></b> Chronic pain is a debilitating condition that imposes a tremendous burden on health-care systems around the world. While frontline treatments for chronic pain involve pharmacological and psychological approaches, neuromodulation can be considered for treatment-resistant cases. Neuromodulatory approaches for pain are diverse in both modality and target and their mechanism of action is incompletely understood. <b><i>Objectives:</i></b> The objectives of this study were to (i) understand the current landscape of pain neuromodulation research through a comprehensive survey of past and current registered clinical trials (ii) investigate the network underpinnings of these neuromodulatory treatments by performing a connectomic mapping analysis of cortical and subcortical brain targets that have been stimulated for pain relief. <b><i>Methods:</i></b> A search for clinical trials involving pain neuromodulation was conducted using 2 major trial databases (ClinicalTrials.gov and the International Clinical Trials Registry Platform). Trials were categorized by variables and analyzed to gain an overview of the contemporary research landscape. Additionally, a connectomic mapping analysis was performed to investigate the network connectivity patterns of analgesic brain stimulation targets using a normative connectome based on a functional magnetic resonance imaging dataset. <b><i>Results:</i></b> In total, 487 relevant clinical trials were identified. Noninvasive cortical stimulation and spinal cord stimulation trials represented 49.3 and 43.7% of this count, respectively, while deep brain stimulation trials accounted for <3%. The mapping analysis revealed that superficial target connectomics overlapped with deep target connectomics, suggesting a common pain network across the targets. <b><i>Conclusions:</i></b> Research for pain neuromodulation is a rapidly growing field. Our connectomic network analysis reinforced existing knowledge of the pain matrix, identifying both well-described hubs and more obscure structures. Further studies are needed to decode the circuits underlying pain relief and determine the most effective targets for neuromodulatory treatment.

Connectomic neuromodulation for Alzheimer’s disease: A systematic review and meta-analysis of invasive and non-invasive techniques

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“…For studies where the outcome was presented as a graph without a numerical summary estimate, a validated plot digitizing tool (WebPlotDigitizer) [30,31] was used to extract numerical data for analysis. For connectomic analysis, we performed seed-to-voxel functional connectivity mapping of DBS and non-invasive neuromodulation targets using well-established methods previously described [17,32].…”

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“…The published literature is also known to suffer from biases towards positive results, which may lead to an overrepresentation of success stories and relative omission of negative trials [21]. Our group has recently sought to address this gap by canvassing clinical trial registries for studies involving neurosurgical interventions such as DBS and spinal cord stimulation [22,23], and for trials using varied neuromodulatory techniques to relieve pain [24].…”