Central Post-Stroke Pain: An Integrative Review of Somatotopic Damage, Clinical Symptoms, and Neurophysiological Measures

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Central Post-Stroke Pain: An Integrative Review of Somatotopic Damage, Clinical Symptoms, and Neurophysiological Measures

Daniel Fernando Arias Betancur^1,2, Maria da Graça Lopes Tarragó³, Iraci Lucena da Silva Torres^1,4, Felipe Fregni⁵ and Wolnei Caumo^1,2,6,7*

• ¹Graduate Program in Medical Sciences, School of Medicine, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
• ²Laboratory of Pain & Neuromodulation, Clinical Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
• ³Physical Medicine and Rehabilitation Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
• ⁴Pharmacology of Pain and Neuromodulation: Pre-clinical Investigations Research Group, Federal University of Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil
• ⁵Laboratory of Neuromodulation and Center for Clinical Research Learning, Physics, and Rehabilitation Department, Spaulding Rehabilitation Hospital, Boston, MA, United States
• ⁶Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
• ⁷Department of Surgery, School of Medicine, Federal University of Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil

Introduction: The physiopathology of central post-stroke pain (CPSP) is poorly understood, which may contribute to the limitations of diagnostic and therapeutic advancements. Thus, the current systematic review was conducted to examine, from an integrated perspective, the cortical neurophysiological changes observed via transcranial magnetic stimulation (TMS), focusing on the structural damage, and clinical symptoms in patients with CPSP.

Methods: The literature review included the databases EMBASE, PubMed, and ScienceDirect using the following search terms by MeSH or Entree descriptors: [(“Cerebral Stroke”) AND (“Pain” OR “Transcranial Magnetic Stimulation”) AND (“Transcranial Magnetic Stimulation”)] (through September 29, 2020). A total of 297 articles related to CPSP were identified. Of these, only four quantitatively recorded cortical measurements.

Results: We found four studies with different methodologies and results of the TMS measures. According to the National Institutes of Health (NIH) guidelines, two studies had low methodological quality and the other two studies had satisfactory methodological quality. The four studies compared the motor threshold (MT) of the stroke-affected hemisphere with the unaffected hemisphere or with healthy controls. Two studies assessed other cortical excitability measures, such as cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). The main limitations in the interpretation of the results were the heterogeneity in parameter measurements, unknown cortical excitability measures as potential prognostic markers, the lack of a control group without pain, and the absence of consistent and validated diagnosis criteria.

Conclusion: Despite the limited number of studies that prevented us from conducting a meta-analysis, the dataset of this systematic review provides evidence to improve the understanding of CPSP physiopathology. Additionally, these studies support the construction of a framework for diagnosis and will help improve the methodological quality of future research in somatosensory sequelae following stroke. Furthermore, they offer a way to integrate dysfunctional neuroplasticity markers that are indirectly assessed by neurophysiological measures with their correlated clinical symptoms.

Introduction

Stroke is the second leading cause of death in the world (1, 2). Among those who survive, motor and somatosensory sequelae compromise the functional capacity and quality of life in many individuals (3–5). In general, one can define two types of pain after stroke: pain associated with peripheral mechanisms (e.g., musculoskeletal, spastic pain, headache, and shoulder pain) and neuropathic central post-stroke pain (CPSP) (6). Although, CPSP is one of the primary sequelae following stroke, there is a gap in understanding its pathophysiology and a diagnostic definition (7). Dejerine and Roussy (8) performed the first description of CPSP in 1906. They described the clinical–anatomical correlation of patients diagnosed with a thalamic stroke who presented a syndrome characterized by intense pain, changes in superficial and deep sensorial perception, mild hemiplegia, choreoathetoid movements, astereognosis, and hemiataxia. Initial studies have linked CPSP to stroke in the thalamus, specifically the pulvinar, the ventral posteromedial, and posterolateral nuclei (9, 10). However, later studies described CPSP in lesions located in the lateral medulla (11), lenticulo-capsular area (12), pons, and in cortical areas (insula and operculum) (13, 14).

Although, there has been enormous progress in stroke treatment in recent decades, the rehabilitation of those who survive a stroke remains a challenge, specifically the recovery of disability, and well-being. Among these sequelae is CPSP, which has been shown to be slightly improved by pharmacological treatments. There is limited literature concerning this neuropathic pain category, primarily focusing on diagnosis and treatment. Thus, a better understanding of the neuroplasticity process might help progress in this field. In this regard, there is an urgent need to conduct studies investigating markers with diagnostic and prognostic potential to assist in the treatment of CPSP. This systematic review aimed to gather data from the literature concerning the physiopathology of CPSP and to critically examine these data to assist in planning future studies that may be able to help in the neurorehabilitation and optimization of functional recovery in individuals affected by CPSP. Specifically, the current review explored, from an integrative perspective, the relationships of the anatomical areas, clinical symptoms, and the cortical excitability (CE) parameters indexed by transcranial magnetic stimulation (TMS) measures. The TMS measures included motor threshold (MT), motor evoked potential (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). From this dataset, we hope to offer additional information to advance this field of knowledge and open a new avenue for the treatment and rehabilitation of individuals affected by CPSP.