Efficacy of adding transcranial electrical stimulation to monopharmacotherapy in post-COVID syndrome with chronic fatigue and cognitive decline

A prospective randomized, double-blind placebo-controlled study to evaluate the effectiveness of neuroprotective therapy using functional brain MRI in patients with post-covid chronic fatigue syndrome

BACKGROUND: The study of potential therapeutic approaches for post-COVID syndrome within randomized controlled trials remains one of the priority objectives. AIM: This study aimed to evaluate the effect of transcranial electrical stimulation as an adjunct to monopharmacotherapy on depression, sleep disturbances, and plasma cortisol and serotonin levels in patients with post-COVID syndrome. METHODS: The study included 150 patients with post-COVID syndrome randomized into two groups (75 each): the main group received transcranial electrical stimulation in addition to monopharmacotherapy, while the reference group received monopharmacotherapy alone. Treatment efficacy was assessed after 15 days using the HADS-D, ISI, CGI-S scales and plasma cortisol and serotonin levels. RESULTS: After 15 days, statistically significant differences between the groups were observed in median scores on HADS-D (p=0.042), CGI-S (p=0.002), and ISI (p 0.001), as well as in cortisol (p=0.001) and serotonin (p=0.002) levels. The addition of transcranial electrical stimulation to monopharmacotherapy in patients with post-COVID syndrome resulted in complete remission of its manifestations in 95% of cases. CONCLUSION: The findings support the use of transcranial electrical stimulation as an effective and pathogenetically justified component of comprehensive treatment in outpatients with post-COVID syndrome presenting with depressive symptoms and sleep disturbances.

Patients suffering from chronic fatigue syndrome (CFS) or post-COVID syndrome (PCS) exhibit a reduced physiological performance capability. Impaired mitochondrial function and morphology may play a pivotal role. Thus, we aimed to measure the muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity and assess mitochondrial morphology in CFS and PCS patients in comparison to healthy controls (HCs). Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers using high-resolution respirometry. Mitochondrial morphology (subsarcolemmal/intermyofibrillar mitochondrial form/cristae/diameter/circumference/area) and content (number and proportion/cell) were assessed via electron microscopy. Analyses included differences in OXPHOS between HC, CFS, and PCS, whereas comparisons in morphology/content were made for CFS vs. PCS. OXPHOS capacity of complex I, which was reduced in PCS compared to HC. While the subsarcolemmal area, volume/cell, diameter, and perimeter were higher in PCS vs. CFS, no difference was observed for these variables in intermyofibrillar mitochondria. Both the intermyofibrillar and subsarcolemmal cristae integrity was higher in PCS compared to CFS. Both CFS and PCS exhibit increased fatigue and impaired mitochondrial function, but the progressed pathological morphological changes in CFS suggest structural changes due to prolonged inactivity or unknown molecular causes. Instead, the significantly lower complex I activity in PCS suggests probably direct virus-induced alterations.

The aim of the present study was to investigate the protective effect of β-carotene on gastric mucosal lesions caused by ischemia-reperfusion (I/R) injury in rat. Forty male rats were randomly divided into sham, control (I/R injury) and three β-carotene-pretreated groups. To induce the I/R lesions, the celiac artery was clamped for 30 min. The clamp was then removed to allow reperfusion for three hours. Pretreated-rats received β-carotene (15, 30 or 60 mg/kg daily, i.p.) or vehicle for five days before the induction of the I/R injury. Samples of gastric mucosa were collected to measure the mRNA expression of IL-1β, TNF-α and TGF-β by quantitative, real-time PCR. Pretreatment with β-carotene decreased the total area of gastric ulcer and mRNA expression, as well as plasma levels of pro-inflammatory cytokines, IL-1β and TNF-α, in a dose-dependent manner. The gene expression and plasma levels of the anti-inflammatory cytokine, TGF-β, were significantly increased in β-carotene-pretreated groups compared with the control. Our findings showed that the protective effect of β-carotene may be mediated partly by reducing mRNA expression and plasma levels of IL-1β and TNF-α, and concurrently, by increasing gene expression and plasma levels of the anti-inflammatory cytokine TGF-β. These findings suggest that β-carotene has a protective role in gastric mucosa. Further clinical and in vivo studies need to be undertaken to support this hypothesis.

Memory decline correlates with increased plasma cytokines in amyloid-beta (1-42) rat model of Alzheimer's disease.

Fatigue is one of the most frequent and disabling symptoms of the post-COVID syndrome. In this study, we aimed to assess the effects of transcranial direct current stimulation on fatigue severity in a group of patients with post-COVID syndrome and chronic fatigue. We conducted a double-blind, parallel-group, sham-controlled study to evaluate the short-term effects of anodal transcranial direct current stimulation (2 mA, 20 min/day) on the left dorsolateral prefrontal cortex. The modified fatigue impact scale score was used as the primary endpoint. Secondary endpoints included cognition (Stroop test), depressive symptoms (Beck depression inventory) and quality of life (EuroQol-5D). Patients received eight sessions of transcranial direct current stimulation and were evaluated at baseline, immediately after the last session, and one month later. Forty-seven patients were enrolled (23 in the active treatment group and 24 in the sham treatment group); the mean age was 45.66 ± 9.49 years, and 37 (78.72%) were women. The mean progression time since the acute infection was 20.68 ± 6.34 months. Active transcranial direct current stimulation was associated with a statistically significant improvement in physical fatigue at the end of treatment and 1 month as compared with sham stimulation. No significant effect was detected for cognitive fatigue. In terms of secondary outcomes, active transcranial direct current stimulation was associated with an improvement in depressive symptoms at the end of treatment. The treatment had no effects on the quality of life. All the adverse events reported were mild and transient, with no differences between the active stimulation and sham stimulation groups. In conclusion, our results suggest that transcranial direct current stimulation on the dorsolateral prefrontal cortex may improve physical fatigue. Further studies are needed to confirm these findings and optimize stimulation protocols.

Background/Objectives: Post-infectious syndromes, including Post-COVID syndrome, Chronic Fatigue Syndrome, and late-stage Lyme disease, are associated with overlapping clinical features and autonomic dysfunction. Despite shared symptoms such as fatigue and orthostatic intolerance, the underlying pathophysiology and specific patterns of autonomic dysfunction may differ. This study aimed to evaluate and compare autonomic nervous system function in these syndromes using multiple diagnostic modalities to identify unique characteristics and improve differentiation between these conditions. Methods: This cross-sectional study included 758 patients, which were divided into four groups: Post-COVID syndrome, Chronic Fatigue Syndrome following Post-COVID syndrome, Chronic Fatigue Syndrome unrelated to COVID-19, and late-stage Lyme disease. Autonomic nervous system function was assessed using cardiovascular reflex tests, the Head-Up Tilt Test, beat-to-beat analysis, five-minute electrocardiogram recordings, 24 h Holter electrocardiogram monitoring, and 24 h ambulatory blood pressure monitoring. Statistical analyses compared parameters across the groups, focusing on patterns of sympathetic and parasympathetic dysfunction. Results: The patients with Lyme disease showed distinct autonomic patterns, including a higher prevalence of orthostatic hypotension (53.4%) and changes in heart rate variability during the Head-Up Tilt Test suggestive of adrenergic failure. Compared to the other groups, patients with Lyme disease exhibited reduced baroreceptor sensitivity and diminished changes in frequency domain heart rate variability parameters during orthostatic stress. Parasympathetic dysfunction was less prevalent in the Lyme disease group, while the Post-COVID syndrome and Chronic Fatigue Syndrome groups showed more pronounced autonomic imbalances. Conclusions: The patients with Post-COVID syndrome, Chronic Fatigue Syndrome, and late-stage Lyme disease exhibited varying degrees and types of autonomic dysfunction. Late-stage Lyme disease is characterized by adrenergic failure and distinct hemodynamic responses, differentiating it from other syndromes. The functional assessment of autonomic nervous system function could aid in understanding and managing these conditions, offering insights for targeted therapeutic interventions.

Coronavirus disease 2019 (COVID-19) is still a major medical concern. Patients who have recovered from the infection from COVID-19 face the ordeal of post-covid syndrome. In these patients, there is a decrease in physical abilities, in particular musculoskeletal complications and post-traumatic stress, depression and chronic fatigue, which impair their quality of life. This necessitates long-term rehabilitation, which supports recovery after hospitalization. Treatment through movement is part of the rehabilitation measures contributing to the functional recovery of patients with post-covid syndrome. To study how the functional capabilities of these patients improve and how their quality of life is affected, we created a set of physical exercises to be performed at home for 6 months. At baseline and at the end of the study, patients completed the SF-36 quality of life questionnaire. The aim of the study was to track the changes in the quality of life of patients with post-covid syndrome by influencing their functional state. Our study found a decline in the quality of life of the examined patients. After the application of the kinesitherapy program, the functional status of the patients improved, their functional independence was optimized, which contributed to the improvement of the quality of life of the post-covid patients syndrome.

Expression of proinflammatory cytokines in the failing human heart: comparison of recent-onset and end-stage congestive heart failure

Pro-inflammatory cytokines are associated with systemic inflammatory responses. To investigate the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) compared to healthy individuals. This case-control study was conducted on 30 patients with NAFL, 30 patients with NASH, and 30 healthy volunteers. The plasma level of IL-1β, IL-6, and TNF-α were determined by ELISA, and biochemical parameters were measured using colorimetric methods. IL-1β and IL-6 levels were significantly higher in patients with NASH compared with NAFL and control group. However, TNF-α levels had no significant variations in NAFL and NASH patients compared to the control group (p=0.903 and p=0.960, respectively). Results showed that the levels of ALT activity and pro-inflammatory cytokines were higher in patients with NASH compared to control and NAFL subjects; Therefore, steatosis and inflammation develop as a result of excessive pro-inflammatory factors in NASH.

Objective: To assess the effects of allergens on interleukin-18 (IL-18), IL-18 binding protein a (IL-18BPa), and IL-18 receptor α (IL-18Rα) expression levels in different monocyte subtypes of the peripheral blood samples of allergic asthma (AA) patients, and the correlations between the percentage of IL-18+classical monocytes and plasma levels of pro-inflammatory cytokines. Methods: A cross-sectional study. Blood samples were collected from 28 healthy controls and 33 patients experiencing acute attack of AA based on a positive skin prick test of Henan Provincial People's Hospital from February 2023 to April 2024. Flow cytometry was used to assess the effects of allergens on IL-18, IL-18BPa, and IL-18Rα expression levels in the classical, intermediate, and non-classical monocytes of the peripheral blood samples of AA patients. Kruskal-Wallis test and Pairwise test were used to analyze statistical significance between groups. Plasma tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) levels were estimated using Bioplex assays. Pearson correlation test was used to determine the association between the percentage of IL-18+classical monocytes and the plasma levels of IL-1β and TNF-α. Results: Compared with healthy controls, the percentages of classical and non-classical monocytes in the peripheral blood of AA patients were reduced by 20.2% (Z=-3.89, P<0.001) and 45.8% (Z=-4.01, P<0.001), respectively. Allergens increased the percentages of classical, intermediate, and non-classical monocytes in AA patients in vitro by 13.1%-61.5% (all P<0.05). Compared with healthy controls, the percentages of IL-18 expression in classical monocytes of AA patients was elevated by 1.08-fold (Z=-6.40, P<0.001), whereas the percentages of IL-18 expression in intermediate and non-classical monocytes were reduced by 52.7% (Z=-6.40, P<0.001) and 3.23% (Z=-3.13, P=0.001), respectively. Allergens upregulated IL-18 expression by 16.4%-67.8% in the classical and intermediate monocytes of AA patients (all P<0.05). Compared with healthy controls, IL-18BPa expression level was lower in the three monocyte subtypes of AA patients (all P<0.05). However, allergens upregulated IL-18BPa expression by 8.9% and 13.3% in the classical monocytes (both P<0.05). Compared with healthy controls, IL-18Rα expression was elevated by 1.29-fold in the classical monocytes of AA patients (Z=-6.40, P<0.001). Allergens upregulated IL-18Rα expression by 17.6%-39.2% in the three monocyte subtypes of AA patients (all P<0.05). Plasma levels of IL-1β and TNF-α in the AA patients were increased compared to those in healthy controls (all P<0.001), and correlated with the percentage of IL-18+classical monocytes (r=0.451, 0.714; both P<0.05). Conclusions: Allergens may participate in the inflammatory response of AA by inducing the differentiation of monocytes and the expression levels of IL-18, IL-18BPa and IL-18Rα in different blood monocytes subtypes. Classical monocytes are the potential source of elevated plasma IL-18 level in AA patients.

To assess the degree and interrelationship of sleep disturbance and plasma cytokine levels in temporomandibular disorder (TMD) pain patients. Forty female TMD patients and 20 age-, sex-, and body mass index (BMI)-matched healthy subjects were enrolled. TMD was diagnosed using the Research Diagnostic Criteria for TMD. The TMD patients were classified as having low or high disability according to Graded Chronic Pain Scale findings. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to measure sleep quality. Plasma concentrations of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were measured from blood samples collected between 9 am and noon. Statistical analyses included Kruskal-Wallis and one-way analysis of variance tests to compare results between different groups and multivariate general linear models to evaluate the effect of sleep status on cytokine levels. The high-disability group had the highest PSQI and ESS scores (P < .001). Plasma levels of IL-1β, IL-6, IL-10, and TNF-α were significantly higher in the patient groups, with the high-disability group exhibiting the highest values (P ≤ .001). The plasma cytokine levels were significantly correlated with PSQI scores (P < .05). Plasma levels of IL-10 and TNF-α were significantly associated with the disability level after adjusting for both sleep indices (both P < .05). Patients with TMD, especially those with high disability, had elevated plasma cytokine levels and increased ESS and PSQI scores suggestive of sleep disturbance.

The pathophysiological mechanisms involved in chronic disorders such as complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome have not been clearly defined. The course of the pain in some of the syndromes, the absence of evident tissue damage, and the predominance of alterations in the autonomic nervous system are shared similarities between them. The production of autoantibodies following a trigger in the syndromes was previously described, for instance, trauma in complex regional pain syndrome, infectious agents in fibromyalgia, chronic fatigue syndrome, and post-COVID syndrome, and the immune stimulation by silicone in women with breast implants. In fact, the autoantibodies produced were shown to be directed against the autonomic nervous system receptors, leading to the amplification of the perception of pain alongside various clinical symptoms seen during the clinical course of the syndromes. Therefore, we viewed autoantibodies targeting the autonomic nervous system resulting in autonomic dysfunction as likely the most comprehensive explanation of the pathophysiology of the disorders mentioned. Based on this, we aimed to introduce a new concept uniting complex regional pain syndrome, fibromyalgia, chronic fatigue syndrome, silicone breast implant–related symptoms, and post-COVID syndrome, namely “autoimmune autonomic dysfunction syndromes”. Due to its etiological, pathophysiological, and clinical implications, the suggested term would be more precise in classifying the syndromes under one title. The new title would doubtlessly facilitate both laboratory and clinical studies aimed to improve diagnosis and make treatment options more directed and precise.

Multiple studies support a role for inflammation in the pathogenesis of coronary atherosclerosis and unstable cardiac syndromes. However, of the known proinflammatory cytokines, only elevated plasma levels of interleukin-6 have been linked to unstable angina. We sought to examine the plasma levels of other major proinflammatory cytokines in similar clinical settings and to determine the extent of the relationship between inflammation and unstable coronary syndromes by measuring the levels of various proinflammatory cytokines in patients with stable and unstable angina. We measured plasma levels of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) in 97 patients: 67 with stable angina, 24 with unstable angina, and 15 healthy controls. Mean levels of IL-1beta were significantly higher in patients with unstable angina as compared to patients with stable angina (p =.009). Levels of IL-6 were significantly higher than control patients for both stable angina and unstable angina patients (p =.031 and.006, respectively). No significant differences were found in the levels of TNF-alpha. Our results suggest that both IL-1beta and IL-6 contribute to the pathogenesis of unstable angina, and that the profile of circulating plasma levels of proinflammatory cytokines differs in unstable angina from that in stable angina. Abbreviated Abstract. Multiple studies support a role for inflammation in the pathogenesis of coronary atherosclerosis and unstable cardiac syndromes. We measured plasma levels of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) in patients with stable and unstable coronary syndromes. Levels of IL-1beta and IL-6 were found to be elevated in patients with unstable coronary syndromes. No significant differences were found in the levels of TNF-alpha. Our results suggest that both IL-1beta and IL-6 contribute to the pathogenesis of unstable angina.

Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses