---
title: "Central sensitization in Long COVID: links to autonomic symptom burden, cerebral hypoperfusion, an"
id: "pubmed-42308676"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42308676"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42308676/"
doi: "10.1016/j.jns.2026.126058"
published_at: "2026-09-15T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Central sensitization in Long COVID: links to autonomic symptom burden, cerebral hypoperfusion, an
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42308676
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42308676/)
- **DOI:** [10.1016/j.jns.2026.126058](https://doi.org/10.1016%2Fj.jns.2026.126058)
- **Published At:** 2026-09-15T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- This study assessed **central sensitization** (CS) in 169 consecutive patients with Long COVID referred for orthostatic intolerance evaluation, using the Central Sensitization Inventory and multiple objective tests. - CS was identified in 81% of participants, and those with CS were more often female (79.6% vs. 53.1%, p = 0.004). - Patients with CS had higher rates of anxiety, depression, fibromyalgia, and headaches and showed greater autonomic, sensory, and global health symptom burden (all p < 0.001) per COMPASS-31, NTSS-6, and PROMIS surveys. - Objective autonomic testing included deep breathing, Valsalva maneuver, and head-up tilt with transcranial Doppler and capnography monitoring; autonomic failure frequency was similar in both groups (84.7% vs. 84.4%, p = 0.999). - Patients with CS exhibited a larger decline in orthostatic cerebral blood flow velocity (-25.53% ± 11.19 vs. -22.09% ± 10.53, p = 0.038), indicating greater **cerebral hypoperfusion** during orthostasis. - Interleukin-6 levels were higher in the CS group (p = 0.041), consistent with possible **neuroinflammation** associated with CS in Long COVID. - Skin biopsy results for small-fiber assessment showed comparable prevalence of abnormal findings in CS and non-CS groups (50.8% vs. 52.0%, p = 0.999). - The authors conclude that **central sensitization** is highly prevalent in this Long COVID cohort and may contribute to multisystem symptomatology; cerebral hypoperfusion and neuroinflammation are proposed pathophysiological contributors. - The report documents study methods and key statistical comparisons; further details beyond the abstract (e.g., full protocol, longitudinal outcomes, or treatment implications) were not reported in the provided source text.
## Clinical Analysis & Structured Key Points
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Epub 2026 Jun 12. # Central sensitization in long COVID: Associations with autonomic symptom burden, cerebral hypoperfusion, and neuroinflammation [Peter Novak](https://pubmed.ncbi.nlm.nih.gov/?term=Novak+P&cauthor_id=42308676)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42308676/#full-view-affiliation-1 "Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. Electronic address: pnovak2@bwh.harvard.edu."), [Ramya S Iyer](https://pubmed.ncbi.nlm.nih.gov/?term=Iyer+RS&cauthor_id=42308676)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42308676/#full-view-affiliation-2 "Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. Electronic address: iyer.ramy@northeastern.edu.") Affiliations Expand ### Affiliations * 1 Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. Electronic address: pnovak2@bwh.harvard.edu. * 2 Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. Electronic address: iyer.ramy@northeastern.edu. * PMID: **42308676** * DOI: [ 10.1016/j.jns.2026.126058 ](https://doi.org/10.1016/j.jns.2026.126058) Item in Clipboard # Central sensitization in long COVID: Associations with autonomic symptom burden, cerebral hypoperfusion, and neuroinflammation Peter Novak et al. J Neurol Sci. 2026. Show details Display options Display options Format Abstract PubMed PMID J Neurol Sci Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22J+Neurol+Sci%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22J+Neurol+Sci%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42308676/) . 2026 Sep 15:488:126058. doi: 10.1016/j.jns.2026.126058. Epub 2026 Jun 12. ### Authors [Peter Novak](https://pubmed.ncbi.nlm.nih.gov/?term=Novak+P&cauthor_id=42308676)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42308676/#short-view-affiliation-1 "Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. Electronic address: pnovak2@bwh.harvard.edu."), [Ramya S Iyer](https://pubmed.ncbi.nlm.nih.gov/?term=Iyer+RS&cauthor_id=42308676)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42308676/#short-view-affiliation-2 "Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. Electronic address: iyer.ramy@northeastern.edu.") ### Affiliations * 1 Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. Electronic address: pnovak2@bwh.harvard.edu. * 2 Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. Electronic address: iyer.ramy@northeastern.edu. * PMID: **42308676** * DOI: [ 10.1016/j.jns.2026.126058 ](https://doi.org/10.1016/j.jns.2026.126058) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract **Background:** The mechanisms driving the broad spectrum of Long COVID symptoms-such as fatigue, brain fog, pain, and dysautonomia-remain uncertain. This study investigated central sensitization (CS) as a potential contributor to symptom burden in patients with Long COVID. We aimed to examine its association with symptom severity, as well as objective cerebrovascular, autonomic, and inflammatory markers. **Methods:** A total of 169 consecutive patients with Long COVID referred for evaluation of orthostatic intolerance underwent assessment using the Central Sensitization Inventory, symptom burden surveys (autonomic: COMPASS-31; sensory: NTSS-6; global health: PROMIS), autonomic function testing (deep breathing, the Valsalva maneuver and head-up tilt test with transcranial Doppler and capnography monitoring), and skin biopsies for small-fiber assessment. **Results:** CS was present in 81% of participants. Patients with CS were more often female (79.6% vs. 53.1%, p = 0.004) and had higher rates of anxiety, depression, fibromyalgia and headaches, as well as a significantly greater autonomic, sensory and global health symptom burden (all p < 0.001). Compared with patients without CS, they also exhibited a greater decline in orthostatic cerebral blood flow velocity (-25.53% ± 11.19 vs. -22.09% ± 10.53, p = 0.038) and higher interleukin-6 levels (p = 0.041). Autonomic failure, most commonly of mild grade, occurred at similar frequency in both groups (84.7% vs. 84.4%, p = 0.999). Skin biopsies demonstrated a comparable prevalence of abnormal findings in both groups (50.8% vs. 52.0%, p = 0.999). **Conclusion:** Central sensitization appears highly prevalent among patients with Long COVID and may contribute to their multisystem symptomatology. Cerebral hypoperfusion, and neuroinflammation may constitute pathophysiological mechanisms underlying central sensitization in this population. **Keywords:** Central sensitization syndrome; Dysautonomia; Long COVID; QASAT. Copyright © 2026 Elsevier B.V. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest PN is a current or previous shareholder of Moderna, Novo Nordisk and Hims & Hers Health. PN received royalties from Oxford University Press and is advisor - independent Contractor for Dysimmune Diseases Foundation. ## Similar articles * [ Orthostatic intolerance with tachycardia (postural tachycardia syndrome) and without (hypocapnic cerebral hypoperfusion) represent a spectrum of the same disorder. ](https://pubmed.ncbi.nlm.nih.gov/39544990/) Novak P, Systrom DM, Witte A, Marciano SP.Novak P, et al.Front Neurol. 2024 Oct 30;15:1476918. doi: 10.3389/fneur.2024.1476918. eCollection 2024.Front Neurol. 2024.PMID: 39544990Free PMC article. * [ Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19. ](https://pubmed.ncbi.nlm.nih.gov/34952975/) Novak P, Mukerji SS, Alabsi HS, Systrom D, Marciano SP, Felsenstein D, Mullally WJ, Pilgrim DM.Novak P, et al.Ann Neurol. 2022 Mar;91(3):367-379. doi: 10.1002/ana.26286. Epub 2022 Jan 18.Ann Neurol. 2022.PMID: 34952975Free PMC article. * [ Role of Central Sensitization Syndrome in Patients With Autonomic Symptoms. ](https://pubmed.ncbi.nlm.nih.gov/40190589/) Novak P, Marciano SP, Witte A.Novak P, et al.Neurol Clin Pract. 2025 Jun;15(3):e200463. doi: 10.1212/CPJ.0000000000200463. Epub 2025 Apr 3.Neurol Clin Pract. 2025.PMID: 40190589Free PMC article. * [ The pivotal role of central sensitization in long COVID, fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. ](https://pubmed.ncbi.nlm.nih.gov/40512228/) Goldenberg DL.Goldenberg DL.Expert Rev Neurother. 2025 Aug;25(8):973-989. doi: 10.1080/14737175.2025.2516097. Epub 2025 Jun 13.Expert Rev Neurother. 2025.PMID: 40512228Review. * [ Long COVID: emerging pathophysiological mechanisms. ](https://pubmed.ncbi.nlm.nih.gov/40105889/) Mueller MR, Ganesh R, Beckman TJ, Hurt RT.Mueller MR, et al.Minerva Med. 2025 Apr;116(2):156-165. doi: 10.23736/S0026-4806.25.09539-4. Epub 2025 Mar 19.Minerva Med. 2025.PMID: 40105889Review. 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