Sequential transcranial electrical stimulation in patients with dyscirculatory encephalopathy associated with post-COVID syndrome

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BACKGROUND

Chronic cerebrovascular insufficiency (discirculatory encephalopathy) is characterized by slowly progressive morphofunctional brain impairments and presents clinically with a pattern of neurological and neuropsychological disorders. The leading etiopathogenetic factors include microangiopathy, endothelial dysfunction, altered cerebral metabolism, and blood rheology, typically arising in the context of comorbid conditions [1–3]. Post-COVID syndrome is known to exacerbate anxiety, depression, and cognitive impairments [4–6], significantly worsening the clinical course of discirculatory encephalopathy by 1.3–2.2 times [7].

Therefore, medical rehabilitation for discirculatory encephalopathy associated with post-COVID syndrome should be comprehensive, integrating measures in accordance with clinical guidelines on cognitive impairment [8], rehabilitation for post-COVID syndrome [9], and the introduction of effective neurotropic medical technologies [10–12], such as transcranial electrical stimulation therapy. This approach may help prevent disease progression and address cognitive, emotional, and locomotor dysfunctions.

Despite the wide use of transcranial stimulation technologies in rehabilitation for discirculatory encephalopathy [13–16], their differentiated therapeutic effects and the potential for combined or simultaneous use remain unclear. The primary hypothesis underlying the use of sequential transcranial electrical stimulation therapy was the potential for a synergistic effect on the central nervous system: on one hand, through the predominant influence of transcranial micropolarization (TCMP) on neocortical neurons, and on the other, through diencephalic brain stimulation (DBS) targeting structures of the limbic system, which may contribute to the restoration of cortico-subcortical connectivity and neurohumoral regulation.

This study aimed to assess the effectiveness of complex medical rehabilitation involving sequential transcranial electrical stimulation therapy in patients with dyscirculatory encephalopathy associated with post-COVID syndrome.

METHODS

Study Design

It was an open-label, prospective, randomized comparative study in a day hospital setting in accordance with ethical standards (Helsinki Declaration, Fortaleza, Brazil, 2013).

Eligibility Criteria

Inclusion criteria: Patients diagnosed with stage I–II discirculatory encephalopathy associated with post-COVID syndrome, scoring 3 points on the rehabilitation routing scale, 3–4 months after COVID-19 infection; signed informed consent for participation and data processing.

Exclusion criteria: General contraindications to physiotherapy; history of inflammatory brain diseases, trauma, or tumors; psychiatric disorders; epilepsy; seizure syndrome; inflammatory eye diseases; grade III hypertension; ischemic heart disease with complex arrhythmias; pacemaker; individual intolerance to the prescribed medications or electrical stimulation.

Withdrawal criteria: Adverse reactions during the study; protocol violations; patient withdrawal of consent.

Study Setting

The study was conducted at the clinical base of the Department of Physical and Rehabilitation Medicine, Federal State Budgetary Educational Institution of Higher Education, Ural State Medical University, Ministry of Health of the Russian Federation, in the day hospital of Nizhnyaya Tura Central City Hospital.

Study Duration

The study was carried out from 2022 to 2023, with a follow-up period of 14 days per patient. Assessment and treatment were conducted before and after the rehabilitation course.

Intervention

The study enrolled 142 patients with discirculatory encephalopathy associated with post-COVID syndrome. Participants were randomized into three groups.

All patients received therapy consisting of a gentle training regimen and standard diet, daily group therapeutic breathing exercises (30 minutes), moderate-intensity walking (1500–2500 m), and general magnetic therapy (Kolibri-Expert device, Russia; Marketing Authorization No. FSR 2011/11030 (ФСР 2011/11030), issued on June 21, 2011) using a traveling pulsed magnetic field with 3.5 mT induction for 20 minutes daily over 10 sessions.

Pharmacologic therapy included the angioprotector pentoxifylline (200 mg three times daily); a cerebral circulation modulator, dry extract of Ginkgo biloba leaves (40 mg three times daily); the anticoagulant Xarelto (2.5 mg twice daily); and the metabolic agent Cytoflavin (2 tablets twice daily).

All three groups underwent sequential transcranial electrical stimulation therapy using the Magnon-2 device (Russia; Marketing Authorization No. RZN 2020/12308 (РЗН 2020/12308)), with variation in electrical pulse modalities:

Group 1 (reference group 1), which included 48 participants, received TCMP using the Magnon-2 device. The anode of the electrode-mask was placed on the forehead at the hairline, and the cathode was positioned in the retromastoid area. After selecting the channels using the current control buttons, a galvanic current of 0.3–0.5 mA was applied.

Group 2 (reference group 2), which included 46 participants, received DBS using the Magnon-2 device. The electrode mask was fixed to the skin of the eyelids and retromastoid area using a cross-polar configuration (two device channels) to produce signal interference. A bipolar current was applied with an initial pulse duration of 0.2 ms: during the first five sessions, the stimulation frequencies were set at 1000 Hz in channel 1 and 990 Hz in channel 2 (interference frequency of 10 Hz). For the subsequent five sessions, the pulse duration was increased to 0.3–0.4 ms, with frequencies adjusted to 200 Hz in channel 1 and 190 Hz in channel 2 (interference frequency of 10 Hz). The current amplitude was increased until patients reported a mild vibration of moderate intensity beneath the electrodes and a more pronounced vibration of moderate strength within the head.

Group 3 (main group), consisting of 48 participants, received electroencephalic therapy using the Magnon-2 device in a sequential manner: first, TCMP was applied for 10–20 minutes, immediately followed by DBS for an additional 10–20 minutes, using the electrical parameters described above.

Sessions were administered daily, lasting 20–40 minutes (increased by 5 minutes each session), for a total of 10 sessions.

Outcomes Registration

Dynamic monitoring included clinical symptoms of discirculatory encephalopathy using a visual analog scale (VAS) from 0 (none) to 10 (maximal severity).

Neuropsychological testing was conducted to assess mental status using validated, high-sensitivity instruments: the Mini-Mental State Examination (MMSE), the Frontal Assessment Battery (FAB), the Clock Drawing and Number Search Tests (Schulte Tables, 1964), the 10 Words test by A.R. Luria (1962), the Hospital Anxiety and Depression Scale (HADS; S. Zigmond, R.P. Snaith, 1983), and the Spielberger State-Trait Anxiety Inventory (STAI, 1976).

Ethics Approval

The study was approved by the local Ethics Committee of the State Budgetary Healthcare Institution Nizhnyaya Tura Central City Hospital (protocol No. 2, dated February 7, 2022).

Statistical Analysis

Data were analyzed using SPSS 13.0 (Mathematica 5.1). Group equivalence was confirmed using the non-parametric Mann–Whitney U test. Quantitative data were compared using the Wilcoxon signed-rank test for paired samples, with a 95% confidence interval (95% CI). Results were considered statistically significant at p <0.05.

RESULTS

Participants

The study involved 142 patients diagnosed with discirculatory encephalopathy associated with post-COVID syndrome who met the inclusion criteria. Among them, 79 were women (55.6%) and 63 were men (44.4%), with a median age of 59 years [95% CI, 45–69]. Disease duration averaged 8.4 years [95% CI, 3–10], and the post-COVID period was 3.6 months [95% CI, 3–4].

At baseline, participants reported the following symptoms: headache (127, 89.4%), tinnitus (122, 85.9%), impaired memory and attention (138, 97.2%), fatigue (95, 66.9%), reduced work capacity (95, 66.9%), irritability/emotional lability (80, 56.3%), depressive mood (56, 39.4%), nonspecific dizziness/unsteadiness (69, 48.6%), and sleep disturbances (127, 89.4%).

Neurological examination revealed focal symptoms such as pupillary light reflex attenuation (131, 92.3%), pathological reflexes (98, 69.0%), coordination disorders such as gait instability and reduced postural stability (99, 69.7%), nystagmus (70, 49.3%), flattened nasolabial folds (79, 55.6%), tongue deviation (63, 44.4%), and facial hypoesthesia/paresthesia (64, 45.0%).

Primary Results

The majority of patients (139/142, 97.9%) tolerated therapy well.

Significant intergroup differences were observed post-treatment (Table 1). In Group 3 (main group), which received combined transcranial electrical stimulation therapy using both methods sequentially (TCMP and DBS), a statistically significant improvement (p < 0.05) in all assessed symptoms of discirculatory encephalopathy was observed compared to baseline, with an increase of 1.2–1.6 times. In Group 1, which received only TCMP, there was a 1.2–1.4-fold reduction (p <0.05) in the severity of cranialgia, memory and attention deficits, irritability, and sleep disturbances. In Group 2, which received DBS as monotherapy, a 1.3–1.4-fold decrease (p <0.05) was observed in tinnitus, fatigue, reduced work capacity, and dizziness. All three groups reported decreased depressive symptoms (1.4–1.6 times; p <0.05).

 

Table 1. Clinical symptom dynamics with patients suffering from dyscirculatory encephalopathy after COVID-19

Clinical symptoms	Т1/Т2	Group
		1 (n=48)	2 (n=46)	3 (n=48)
Cranialgia	n	43	41	46
	1	6.2 [3.7; 7.6]	5.9 [4.7; 7.3]	6.0 [3.5; 7.4]
	2	4.8 [3.1; 6.6]*	4.3 [3.3; 5.8]	3.8 [2.0; 5.4]*
Tinnitus	n	41	40	40
	1	4.9 [3.4; 6.3]	4.9 [3.1; 6.8]	5.2 [3.1; 7.2]
	2	4.0 [2.8; 5.6]	3.8 [2.6; 5.1]*	3.5 [2.6; 4.9]*
Cognitive impairments (memory, attention)	n	46	44	45
	1	5.1 [3.8; 6.4]	5.3 [4.0; 6.5]	5.4 [3.9; 6.8]
	2	4.4 [2.8; 5.9]*	4.0 [2.6; 5.9]	3.6 [2.3; 5.0]*
Reduced work capacity, fatigue	n	32	30	33
	1	6.8 [5.4; 8.1]	7.1 [5.6; 8.7]	7.0 [5.6; 8.4]
	2	6.2 [5.1; 7.3]	5.3 [4.2; 6.5]*	4.4 [3.8; 5.1]*. #
Irritability	n	28	25	27
	1	4.7 [3.0; 6.4]	4.5 [3.2; 5.9]	3.9 [3.3; 7.1]
	2	3.6 [2.5; 4.7]*	4.3 [2.9; 5.7]	3.3 [2.5; 5.7]*
Depressed mood	n	19	16	21
	1	4.8 [2.4; 7.1]	5.0 [2.6; 7.4]	5.2 [2.4; 7.1]
	2	3.5 [2.1; 5.0]*	3.6 [2.0; 5.3]*	3.2 [2.3; 4.1]*
Dizziness	n	25	22	22
	1	6.7 [5.3; 8.1]	6.5 [5.1; 7.9]	6.7 [5.6; 7.8]
	2	6.2 [4.8; 7.6]	5.1 [3.9; 6.4]*	4.3 [3.6; 5.1]*. #
Dissomnia	n	43	42	42
	1	5.2 [3.5; 6.9]	5.2 [3.3; 7.1]	5.0 [3.4; 6.7]
	2	4.1 [2.8; 5.4]*	4.7 [2.9; 6.4]	3.6 [2.3; 4.8]*

Note. * Significant differences in the pre-treatment and post-treatment group, р <0,05. Т1/Т2 ― pre-/post-treatment.

 

A comparative analysis of neuropsychological test scores in patients with discirculatory encephalopathy following COVID-19 revealed a similar pattern across the assessed parameters (Table 2). Group 3 demonstrated a reduction in all psychophysiological disturbances (by 1.1–2.0 times; p < 0.05); in Group 1, improvements were observed in the total MMSE score (by 1.1 times; p <0.05), FAB score (by 1.1 times; p <0.05), Schulte table performance (by 1.1 times; p <0.05), and the 10 Words test (by 1.4 and 1.5 times for immediate and delayed recall, respectively; p <0.05). In Group 2, a reduction in mental instability was noted based on Schulte tables (by 1.8 times; p < 0.05), anxiety and depression scores on the HADS (by 1.7 and 1.5 times, respectively; p <0.05), and reactive and trait anxiety scores in the STAI (by 1.4 and 1.2 times, respectively; p < 0.05). Clock drawing scores improved significantly in all groups (1.3–1.5 times; p <0.05).

 

Table 2. Dynamics of neuropsychological test results with the patients suffering from dyscirculatory encephalopathy after COVID-19

Measure, Total Score		Т1/Т2	Group
			1 (n=48)	2 (n=46)	3 (n=48)
MMSE		1	25 [23; 28]	26 [23; 29]	26 [24; 28]
		2	27 [25; 29]*	26 [24; 29]	28 [28; 29]*
FAB		1	15 [13; 17]	14 [12; 18]	14 [12; 16]
		2	16 [14; 18]*	14 [12; 18]	15 [14; 17]*
Schulte tables	Task efficiency	1	2 [1; 2]	2 [1; 2]	2 [1; 2]
		2	2 [1; 3]*	3 [1; 3]	3 [2; 3]*
	Mental stability	1	1.2 [0.8; 1.5]	1.3 [0.9; 1.4]	1.4 [0.9; 1.6]
		2	0.9 [0.6; 1.3]	0.7 [0.5; 1.0]*	0.7 [0.4; 1.1]*
10 Words test	Immediate recall	1	5 [5; 7]	5 [5; 7]	6 [5; 7]
		2	7 [6; 8]*	6 [5; 8]	7 [6; 8]*
	Delayed recall	1	4 [3; 6]	4 [3; 6]	5 [3; 7]
		2	6 [6; 7]*	4 [3; 7]	6 [6; 7]*
lock Drawing test		1	6 [5; 7]	6 [6; 7]	6 [5; 7]
		2	8 [7; 9]*	9 [7; 10]*	8 [7; 9]*
HADS	Anxiety	1	11 [8; 14]	12 [9; 13]	13 [10; 15]
		2	10 [8; 12]	7 [5; 9]*	8 [6; 10]*
	Depression	1	9 [6; 11]	9 [6; 12]	9 [6; 12]
		2	7 [4; 9]	6 [3; 8]*	6 [4; 8]*
Spielberger– State-Trait Anxiety Inventory (STAI)	Reactive anxiety	1	54 [46; 58]	52 [55; 60]	57 [50; 64]
		2	48 [44; 52]	36 [27; 46]*	40 [31; 48]*
	Trait anxiety	1	45 [29; 58]	41 [26; 59]	43 [28; 56]
		2	40 [30; 48]	33 [25; 44]*	32 [23; 42]*

Note. * Significant differences in the pre-treatment and post-treatment group. р <0.05. Т1/Т2 ― pre-/post-treatment.

 

Adverse Events

During the first DBS session, two patients in Group 2 and one in Group 3 reported discomfort (pressure around the eyes) and subsequently withdrew from the study. These cases were excluded from the statistical analysis.

DISCUSSION

Transcranial electrical stimulation therapy is a group of physiotherapeutic techniques aimed at restoring the functional state of the central nervous system [16, 17]. The therapeutic effects of this type of physiotherapy were identified by V.M. Bogolyubov and Z.S. Khostikoeva [18], who demonstrated that transcranial application of therapeutic physical factors induces generalized response patterns, subsequently activating the body's bioregulatory systems, particularly neurohumoral mechanisms.

The comparative analysis revealed significant differences in therapeutic outcomes among the three approaches to transcranial electrical stimulation therapy in patients with discirculatory encephalopathy associated with post-COVID syndrome. TCMP was most effective in reducing symptoms related to psychosomatic status (headache, impaired memory and attention, irritability, and sleep disturbances) and improving motor and cognitive functions (as assessed by MMSE, FAB, and the 10 Words test). This suggests TCMP may primarily facilitate the restoration of white matter connections between cortical/frontal and subcortical regions. In contrast, DBS proved more effective in addressing psychoneurotic symptoms, such as tinnitus, fatigue, reduced work capacity, and dizziness. These effects were reflected in improvements in HADS (anxiety and depression) and STAI (state and trait anxiety) scores. The deep stimulation produced by the interference of electrical currents in the diencephalic region—including the thalamus, hypothalamus, epithalamus, and subthalamus—appears to reduce the emotional and neurotic burden associated with somatic disorders. It is noteworthy that the combination of these therapeutic modalities in the form of sequential transcranial electrical stimulation therapy (TCMP and DBS) produces pronounced positive clinical and neuropsychological shifts in patients with discirculatory encephalopathy associated with post-COVID syndrome, as confirmed by the comparative statistical analysis of the study outcomes.

The positive effects of transcranial electrical stimulation therapy have been supported by numerous studies conducted by both Russian and international researchers [19–21]. For instance, the regulatory effect of transcranial electrical stimulation therapy on central and peripheral pathogenetic mechanisms of gastroesophageal reflux disease was demonstrated by Sevostyanova et al. [19]. Research led by Shekelle [20] and Price [21] reported favorable outcomes of transcranial electrical stimulation in anxiety and depressive disorders.

Overall, sequential transcranial electrical stimulation therapy (TCMP and DBS) contributes to the reversal of all clinical symptoms and improves neuropsychological test scores by positively influencing cortico-subcortical connectivity in patients with discirculatory encephalopathy associated with post-COVID syndrome.

CONCLUSION

Thus, medical rehabilitation incorporating a combined approach—sequential application of TCMP and DBS—alongside pharmacologic support in patients with discirculatory encephalopathy associated with post-COVID syndrome proved more effective than monotherapy with either modality. This enhanced efficacy is attributed to the pronounced neurotropic action of transcranial electrical stimulation therapy, which enables correction of a broad spectrum of neurological, neuropsychological, and motor impairments.

ADDITIONAL INFORMATION

Funding source. This work was not supported by any external sources of funding.

Competing interests. The authors declare that they have no competing interests.

Authors' contribution. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work. D.A. Ladygin ― review of publications on the subject of the article, writing and editing of the manuscript text, the analysis and interpretation of the review results, selection and examination of the patients, analysis and interpretation of the data; A.A. Fedorov ― concept formation and study design development, analysis and interpretation of the review results, scientific edition of the text of the manuscript; А.S. Kaisinova ― concept formation and study design development, scientific edition of the text of the manuscript; Z.A. Taymazova ― review of the publications on the topic of the article, writing and editing of the text of the manuscript, selection and examination of the patients, analysis and interpretation of the data; N.K. Akhkubekova, R.M. Gusov ― review of the publications on the topic of the article, writing and editing the text of the manuscript, analysis and interpretation of the data.

About the authors

Dmitry A. Ladygin

Ural State Medical University; Nizhneturinsk Central City Clinical Hospital

Email: dmitry.ladygin@inbox.ru
ORCID iD: 0000-0001-6523-1596
Russian Federation, Ekaterinburg; Nizhnyaya Tura

Andrey A. Fedorov

Ural State Medical University; Ekaterinburg Medical Research Centre for Prophylaxis and Health Protection of Industrial Workers

Email: aafedorov@e1.ru
ORCID iD: 0000-0002-9695-2959
SPIN-code: 9728-8397

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Ekaterinburg; Ekaterinburg

Agnessa S. Kaisinova

North Caucasian Federal Scientific and Clinical Center of the Federal Medical and Biological Agency; Pyatigorsk Medical-Pharmaceutical Institute ― A branch of Volgograd State Medical University

Author for correspondence.
Email: zamoms@skfmba.ru
ORCID iD: 0000-0003-1199-3303
SPIN-code: 6552-9684

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Yessentuki; Pyatigorsk

Zarina A. Taymazova

North Caucasian Federal Scientific and Clinical Center of the Federal Medical and Biological Agency; Pyatigorsk Medical-Pharmaceutical Institute ― A branch of Volgograd State Medical University

Email: zarina_taymazova@mail.ru
ORCID iD: 0000-0003-2036-1471
SPIN-code: 1546-1911

MD

Russian Federation, Yessentuki; Pyatigorsk

Nelly K. Akhkubekova

North Caucasian Federal Scientific and Clinical Center of the Federal Medical and Biological Agency

Email: pniik.adm@skfmba.ru
ORCID iD: 0000-0001-7881-7916
SPIN-code: 3008-8175

MD, Dr. Sci. (Medicine)

Russian Federation, Yessentuki

Ruslan M. Gusov

Pyatigorsk Medical-Pharmaceutical Institute ― A branch of Volgograd State Medical University

Email: 61312@mail.ru
ORCID iD: 0000-0002-1582-0138
SPIN-code: 1984-9700

Cand. Sci. (Pharmacy), Associate Professor

Russian Federation, Pyatigorsk

References

Supplementary files