Applications of Non-invasive Neuromodulation for the Management of Disorders Related to COVID-19

Abstract

Background: Novel coronavirus disease (COVID-19) morbidity is not restricted to the respiratory system, but also affects the nervous system. Non-invasive neuromodulation may be useful in the treatment of the disorders associated with COVID-19. Objective: To describe the rationale and empirical basis of the use of non-invasive neuromodulation in the management of patients with COVID-10 and related disorders. Methods: We summarize COVID-19 pathophysiology with emphasis of direct neuroinvasiveness, neuroimmune response and inflammation, autonomic balance and neurological, musculoskeletal and neuropsychiatric sequela. This supports the development of a framework for advancing applications of non-invasive neuromodulation in the management COVID-19 and related disorders. Results: Non-invasive neuromodulation may manage disorders associated with COVID-19 through four pathways: (1) Direct infection mitigation through the stimulation of regions involved in the regulation of systemic anti-inflammatory responses and/or autonomic responses and prevention of neuroinflammation and recovery of respiration; (2) Amelioration of COVID-19 symptoms of musculoskeletal pain and systemic fatigue; (3) Augmenting cognitive and physical rehabilitation following critical illness; and (4) Treating outbreak-related mental distress including neurological and psychiatric disorders exacerbated by surrounding psychosocial stressors related to COVID-19. The selection of the appropriate techniques will depend on the identified target treatment pathway. Conclusion: COVID-19 infection results in a myriad of acute and chronic symptoms, both directly associated with respiratory distress (e.g., rehabilitation) or of yet-to-be-determined etiology (e.g., fatigue). Non-invasive neuromodulation is a toolbox of techniques that based on targeted pathways and empirical evidence (largely in non-COVID-19 patients) can be investigated in the management of patients with COVID-19.

Keywords: COVID-19; NIBS; TMS; coronavirus; neuromodulation; non-invasive vagus nerve stimulation; tDCS; taVNS.

Figure 1

Possible mechanisms of SARS-CoV-2 invasion in the nervous system. SARS-CoV-2 may gain access to the central nervous system via peripheral nerves such as olfactory and vagus nerves. The virus binds to ACE2 receptors, starting the release of cytokines (cytokine storm). This process increases sympathetic activity, which may be responsible for maintaining the inflammatory condition. The presence of co-morbidities such as hypertension, diabetes, coronary artery disease (CAD), increased age, and male sex may contribute to the increased risk of complications. Stimulation of parasympathetic activity via TMS or tDCS at the left dorsolateral prefrontal cortex (F3) or transcutaneous vagus nerve stimulation at the ear may counteract increased sympathetic activity mediated inflammation.

Figure 2

Electrode configurations for non-invasive tDCS, VNS, and rTMS following the 10–20 EEG system. (A) Unilateral tDCS with anode positioned over F3 and cathode over Fp2 on the scalp to modulate the left dorsolateral prefrontal cortex (DLPFC). (B) tDCS using a bifrontal montage to perform anodal stimulation on left DLPFC where the anode is positioned over F3 and cathode is positioned over F4. (C) Anodal tDCS to stimulate the temporal cortex using a bifrontal configuration where the cathode is positioned over T4 and the anode over T3 as seen in (a,b), respectively. (D) Non-invasive vagus nerve stimulation by modulating the cervical branch of the vagus nerve in (a) and the ear in (b). Electrode placement for cervical vagus nerve stimulation is shown in (a). Electrodes are placed at the tragus and the cymba conchae of the left ear to perform unilateral taVNS as shown in (b). (E) rTMS using a figure-8 coil positioned over F3 to stimulate the left DLPFC suggested for high-frequency protocol is shown in (a). Right DLPFC is stimulated using the low-frequency rTMS protocol by placing the coils over F4 as shown in (b).