The effects of transcranial direct current stimulation on vascular, autonomic, and cognitive function in individuals with post-COVID conditions
Creators: name: Somers, Emma R.
Publisher: name: University of Iowa
Year: 2025
Subjects: arterial stiffness
autonomic function
endothelial function
fatigue
macrovascular physiology
transcranial direct current stimulation

description: Background: The SARS-CoV-2 virus is known to bind to angiotensin converting enzyme 2 (ACE2) receptors which are found in the lungs as well as the vascular endothelium. Binding of the virus as well as the downregulation of ACE2 triggers a cytokine storm and disruption of the renin-angiotensin-aldosterone system, leading to an increase in circulating angiotensin 2 (a vasoconstrictor). This heightened state of inflammation and endothelial disruption is taxing on the vascular system and often leads to changes in vascular and hemodynamic outcomes such as increased blood pressure, arterial stiffness, and endothelial dysfunction. These changes have been observed in individuals who have been acutely infected with SARS-CoV-2. However, there is less known about the vascular health of individuals who are beyond acute infection (&gt;4 weeks) and continue to experience COVID-19-related symptoms (primarily fatigue, brain fog). This phenomenon is known as Post-COVID Conditions (PCC), or “long-COVID”. Preliminary data suggest that individuals with PCC continue to display increased arterial stiffness and endothelial dysfunction, as well as autonomic dysfunction, when compared to individuals who have been infected but are not experiencing any persistent symptoms or PCC. The exact reason for this is unknown, and there are conflicting reports of the true state of vascular, autonomic, and cognitive function in individuals with PCC. In an effort to treat the fatigue symptoms of PCC, an electrical brain stimulation known as transcranial direct current stimulation (tDCS) has gained some interest because of its low cost and potential to improve fatigue symptoms by increasing glucose metabolism in the brain. However, there has been limited research on the vascular effects of tDCS. Therefore, this study aimed to investigate the differences in vascular, autonomic, and cognitive function in individuals with PCC compared to individuals without PCC, and to investigate the short-term and long-term effects of M1 anodal tDCS (an excitatory stimulation of the motor cortex of the brain) on vascular, autonomic, and cognitive function outcomes in individuals with PCC.
description: Methods: Vascular, autonomic, and cognitive function was assessed at baseline for individuals with PCC symptoms (SYM, n=12) and individuals without symptoms of PCC (ASYM, n=9). Participants were recruited from the Iowa City community and were matched for age (30-55 years) and date since SARS-CoV-2 infection (1-12 months). Vascular function was assessed as arterial stiffness and endothelial function – arterial stiffness being evaluated with carotid-femoral pulse wave velocity (cfPWV) using non-invasive applanation tonometry, as well as common carotid artery -stiffness using ultrasonography. Endothelial function was evaluated with brachial artery flow-mediated dilation (baFMD) using ultrasonography. Time-to-peak vasodilation (TTP) was assessed from baFMD by determining how many seconds after cuff release the brachial artery became the most dilated. Autonomic function was assessed with cardiovagal baroreflex sensitivity (BRS). Cognitive function was assessed using NIH Toolbox cognitive tests which evaluated executive function with the flanker task, working memory with the list sorting task, and processing speed with the pattern-comparison task. Perceived fatigue was measured using the fatigue assessment scale (FAS), perceived fatiguability was measured using the fatigue severity scale (FSS), objective fatiguability was measured using a 6-minute walk test (6MWT) with rating of perceived exertion (RPE), symptom severity was measured using the COVID-19 symptom severity scale (SSS), pain was measured using the visual analogue scale for pain (VAS), quality of life was measured using the EQ-5D-5L. A blood draw was also taken to assess metabolic and inflammatory markers in plasma. After baseline testing, participants in the SYM group were randomized to receive either four 20-minute consecutive sessions of M1 anodal tDCS (n=5) or four 20-minute consecutive sessions of SHAM (n=5). 24-hours following the intervention, all SYM participants repeated the testing that was completed at baseline. Two follow-up visits with the same testing procedures were conducted on SYM participants at 3- and 6-weeks post-intervention.
description: Results: SYM vs ASYM: At baseline, there were no differences between groups in cfPWV, baFMD (% and mm change), brachial artery baseline diameter, common carotid -stiffness index, carotid AI%, brachial SBP, and brachial DBP (p&gt;0.05). SYM participants reported higher baseline FAS, FSS, SSS, VAS, and lower EQ-5D-5L compared with AYSM participants (p&lt;0.05). However, physical activity levels and 6MWT distance did not differ between groups (p&gt;0.05). There were no significant differences in cardiovagal BRS, executive function, working memory, or processing speed tests at baseline between SYM and ASYM (p&gt;0.05). SYM participants had a significantly higher baseline baFMD time to peak dilation (TTP) in seconds compared to those in the ASYM group (SYM: 61.6  23.1 sec vs. ASYM: 36.8  14.3 sec, p=0.010) tDCS vs SHAM: Following the intervention, there were no significant within-group or between-group differences for change in cfPWV, baFMD (% or mm change), brachial artery baseline diameter, CCA -stiffness index, carotid AI%, brachial SBP, or brachial DBP (p&gt;0.05). There was a significant within-group difference for FMD TTP for the SHAM treatment group, with the average time to peak dilation decreasing after the intervention (-11.6  7.8 sec, p=0.029). This change in TTP was also significantly different between groups compared to the tDCS treatment (tDCS: 6.4  11.5 sec, SHAM: -11.6  7.8 sec, p=0.020). There were no significant within-group or between-group differences in change in cardiovagal BRS (p&gt;0.05). For cognitive function, there was a significant within-group increase in working memory score for the SHAM group following the intervention (9.6  6.8, p=0.022) which was also significant between groups compared to tDCS (tDCS: -5.6  13.0, SHAM: 9.6  6.8, p=0.050), but there were no within-group or between-group differences in change in executive function or processing speed (p&gt;0.05). There were no significant between-group differences in change in perceived fatigue, pain, symptom severity, or quality of life following the intervention (p&gt;0.05). At the 3-week follow-up visit, there was a significant difference in the change of processing speed between the tDCS and SHAM group, with the tDCS group having a mild decrease in score and the SHAM group having a mild increase in score (tDCS: -3.4  3.6, SHAM: 2.8  3.8, p=0.031), however there was no significant within-group difference for either group (p&gt;0.05). Since FSS, 6MWT (m), 6MWT RPE, FMD TTP, and working memory all had significant within-group or between-group results 24-hours following the 4-day intervention, they were also evaluated for sustainability of long-term changes at the 3-week follow-up, but no differences were found (p&gt;0.05).
description: Conclusions: Individuals with PCC present with latent brachial artery vasodilatory responses to a shear stimulus (i.e., TTP) compared with non-PCC controls, a vascular biomarker that is associated with an increased risk of CVD. However, individuals with PCC in our cohort did not exhibit worsened arterial stiffness, baroreflex sensitivity, or cognitive function. Individuals with PCC also self-reported higher levels of perceived fatigue, symptom severity, pain, and lower quality of life compared to controls, but did not differ in objective levels of fatigue or physical activity. M1 anodal tDCS did not result in any major short-term or long-term changes in vascular, baroreflex sensitivity, cognitive, or fatigue outcomes. Altogether, these data suggest that individuals with PCC experienced greater levels of perceived, not objective fatigue, and that these persistent symptoms did not appear to be associated with persistent arterial stiffness, autonomic, or cognitive dysfunction. Our data suggest that tDCS may not be an effective treatment for individuals with PCC, although future studies with a larger sample or longer tDCS intervention would be required to confirm our findings.