Exploring the biomarkers for new-onset chronic pain in long covid. A mechanistic study

An estimated 1.8 million people in UK private households suffer from Long COVID (LC), which refers to the signs and symptoms that persist beyond 4 weeks from the acute phase of COVID-19 infection and cannot be explained by an alternative diagnosis.
Research shows that pain is among the most common post-COVID symptoms, with epidemiological studies suggesting a prevalence of up to 71% in LC patients. LC-chronic pain refers to new-onset pain of musculoskeletal or neuropathic origin that arises following acute infection and remains for longer than 3 months. Only few studies have reported the prevalence of pain symptoms at 3 or more months post-infection, compatible with the criteria for chronic pain . Chronic pain is known to have a significant negative impact on individual health-related quality of life and functional status. The rapidly increasing number of LC cases and associated pain complaints is likely to further contribute to the individual and societal burden of chronic pain. There is an urgent unmet need to investigate underlying pathophysiological mechanisms of LC-chronic pain and potential interventions to alleviate pain-related outcomes in LC patients.
Evidence on the pathological processes underlying the development and maintenance of LC-chronic pain is lacking. A mechanism known to contribute to pain chronification is amplification of neural processing associated with perception of pain within the central nervous system (referred to as central sensitisation), resulting from maladaptive structural and functional changes in central nociceptive pathways (15). This has been shown to contribute to a variety of chronic pain conditions and is likely to also play a role in LC-chronic pain. Several authors have identified potential neurophysiological signatures of pain hypersensitivity in chronic pain patients using electroencephalography (EEG). One strong candidate EEG marker of chronic pain is abnormal alpha activity with chronic pain patients showing lower resting-state alpha activity compared to controls.
Identification of EEG markers of disease opens a promising avenue for research on the therapeutic applicability of targeted non-invasive neuromodulation techniques for the management of pain. One such technique is neurofeedback that entails training to self-regulate one's own neural oscillatory activity, whereby sensory representation of cortical activity is fed back to the individual in real-time. Several studies have reported promising analgesic effects of enhancing alpha power via neurofeedback training or entrainment by external rhythmic stimulation.
The contribution of maladaptive plasticity of central nervous system to pain chronification has not yet been studied in LC. Assessing the presence of EEG markers of chronic pain in LC may help to elucidate underlying pathological processes as well as to identify promising targets of non-invasive personalised therapeutic interventions.
The proposed study consists of:

Work Package WP1: a longitudinal cross-sectional online study using questionnaires to assess pain (severity, location, other characteristics), functioning, psychological variables, demographics and quality of life over a 2-year follow-up period.

Work Package WP2: a case-control study for in-depth EEG analysis of spectral power of different waveforms and event related potentials in LC patients with new-onset chronic pain compared to those without. The association between pain-related outcomes assessed by self-reported questionnaires and EEG markers will be investigated. If EEG markers of LC-chronic pain are identified, an interventional study will be undertaken to explore the potential beneficial effects of a targeted-neurofeedback training in a sample of patients.

The outcomes of this study may be clinically relevant for LC patients and those suffering from primary chronic pain conditions.