Transspinal direct current stimulation with an intensity of 2.5 mA does not affect the corticospinal system excitability and motor skills

Ekaterina D. Pomelova; Помелова Екатерина Дмитриевна; Alyona V.  Popyvanova; Попыванова Алена Владимировна; Dmitry O. Bredikhin; Бредихин Дмитрий Олегович; Maria M. Koriakina; Корякина Мария Михайловна; Anna N. Shestakova; Шестакова Анна Николаевна; Evgeny D. Blagovechtchenski; Благовещенский Евгений Дмитриевич

doi:10.23868/gc545830

Transspinal direct current stimulation with an intensity of 2.5 mA does not affect the corticospinal system excitability and motor skills

Authors: Pomelova E.D.¹, Popyvanova A.V.¹, Bredikhin D.O.¹, Koriakina M.M.¹, Shestakova A.N.¹, Blagovechtchenski E.D.¹
Affiliations:
1. National Research University Higher School of Economics
Issue: Vol 18, No 4 (2023)
Pages: 381-388
Section: Original Study Articles
URL: https://genescells.ru/2313-1829/article/view/545830
DOI: https://doi.org/10.23868/gc545830
ID: 545830

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Abstract

BACKGROUND: Noninvasive brain stimulation effectively affects movements, including the spinal cord level. Stimulation effects are very sensitive to montage and protocols of applied stimulation because they can involve different neuronal mechanisms.

AIM: This study aimed to estimate the effect of anodal transspinal direct current stimulation (tsDCS) with an intensity of 2.5 mA applied at the spinal cord level (C7–Th1 segments) with cervical enlargement on the corticospinal system excitability and motor skills.

METHODS: The study involved 54 healthy adults aged 21.19±3.20 years. The effect of tsDCS was assessed using motorevoked potentials from the first dorsal interosseous (FDI) muscle by transcranial magnetic stimulation in the primary motor cortex before stimulation, immediately after stimulation, and after 15 min.

RESULTS: The application of an 11-min anodal tsDCS with a current value of 2.5 mA at the C7–Th1 level did not affect the motorevoked potentials of FDI. Statistically, changes in motorevoked potentials amplitudes did not differ between groups receiving anodal tsDCS and sham stimulation. In addition, anodal tsDCS did not affect motor skills. An individual’s ability to coordinate fingers and manipulate objects effectively (a measure of dexterity) in the nine-hole peg test and pressing a key in response to a visual stimulus in the serial reaction time task did not differ from that with sham stimulation.

CONCLUSION: 2.5 mA anodal tsDCS on cervical enlargement does not affect the corticospinal system excitability or change motor skills associated with precise hand movements.

Keywords

transspinal direct current stimulation, transcranial magnetic stimulation, motor evoked potentials

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INTRODUCTION

This study aimed to evaluate the possibility of modulating corticospinal system (CSS) excitability using noninvasive transspinal direct current stimulation (tsDCS) while executing precise voluntary movements. Transcranial direct current stimulation is widely used to modulate various cognitive, motor, and sensory functions of the brain at the cortex level [1]; however, data are limited on the use of this type of stimulation protocol at the spinal cord level. This is probably because most protocols related to spinal cord stimulation have a pulse structure (in contrast with cortex stimulation) and affect locomotor activity patterns [2]. However, correcting voluntary movements may require approaches similar to those affecting cognitive functions when there are no strict movement patterns, such as the rhythmic activation of several motoneuronal pools.

The CSS is one of the main human systems associated with the control of precise voluntary movements. It is a unique pathway through which the brain can exert control over certain actions such as voluntary limb movements and fine movements of the fingers and hands [3]. In the CSS, a somatotopic organization exists such that individual pools of neurons in the cerebral cortex are associated with motor neurons that are suitable for certain muscles located in different body parts [4]. With this organization, a change in the activity of one of the parts of the CSS causes selective muscle contractions and ultimately leads to the performance of a certain action (e.g., bending the index finger to press a button) [5]. Selective studies have shown that depending on the electrode location, tsDCS can enhance the corticospinal drive of one muscle preferentially over another, showing the targeting of the tsDCS intervention [6].

CSS excitability can be investigated through motorevoked potentials (MEPs), which can be obtained in target muscles using single-pulse transcranial magnetic stimulation (TMS) in the primary motor cortex (M1). MEP amplitudes provide time-accurate and muscle-specific testing of CSS excitability circuits in the cortex and spinal cord [7, 8].

A previous study showed that tsDCS with an anterior–posterior electrode configuration at the C7 level with a current of 2.0 mA for 20 min increases the amplitudes of MEPs (flexor carpi radialis) up to 2 h after stimulation, although the effects of cathodal and anodal stimulations were not significantly different [9].

Contradictory data showed that tsDCS, both cathodal, and anodal, with anterior–posterior cervical electrode configuration (3 mA, 20 min, C6–T1, biceps brachii, flexor carpi radialis) [10] and with parallel electrode configuration (2.5 mA, 15 min, C3–T3, abductor digit minimi) did not change the amplitudes of MEPs [11]. The varying effects may be due to the differences in the study protocols used, which involved various factors, such as stimulation polarity, electrode installation, and current strength [12]. This study demonstrates the importance of finding more suitable tsDCS parameters to influence responses in the muscles of the upper extremities.

Aim — in this paper, we focused on the effect of tsDCS with an intensity of 2.5 mA on the first dorsal interosseous (FDI) muscles of the upper limb. Specifically, this study aimed to scrutinize the effect of anodal tsDCS, when applied at the spinal cord level with cervical enlargement, on CSS excitability, and the ability of tsDCS to affect motor skills. TMS of M1 is used as a test for CSS excitability. Importantly, because CSS excitability may reflect important aspects related to the control of voluntary movements, we investigated the effects of tsDCS in the context of M1 TMS as a probe and its potential to influence fine voluntary movements.

MATERIAL AND METHODS

Experimental design

The study involved 54 healthy adults aged 21.19±3.2 years. Before inclusion in the study, all participants voluntarily signed an informed consent form, which was approved as part of the study protocol by the HSE Commission for Intrauniversity Surveys and Ethical Evaluation of Empirical Research Projects dated January 19, 2019, with protocol number HSE 19/01/2019. In study 1, participants (n=24) received 11 min of anodal or sham tsDCS at 2.5 mA. The anode electrode was located above the C7–Th1 segments, and the cathode electrode was on the clavicle. The effect of tsDCS was assessed using MEP. To generate MEP, TMS was used in the “hot spot” of the FDI muscle in M1 (controlled using a navigation system) with single impulses whose intensity was 115% of the resting motor threshold in three time intervals before stimulation, after stimulation, and 15 min after stimulation.

The electromyogram was registered with the help of an additional BrainAmp EXG block. Surfаce electromyogrаphy (EMG) was recorded from the right FDI muscles.

In study 2, participants (n=30) received either anodal or sham tsDCS in the same way as for study 1, and during the tsDCS session, the participants performed motor tests, namely, the nine-hole peg test (9-HPT) and the serial reaction time task (SRT). Motor tests were also repeated the next day without stimulation.

Statistical analysis

The modulation of MEPs was evaluated by a linear mixed-effects model. Specifically, the group factor (df=1, stimulation or sham) and time factor (df=2, recordings performed before tsDCS (T_before), immediately after tsDCS (T₀), or 15 min after tsDCS (T₁₅) were used as fixed effects, whereas participant’s ID was used as a random intercept effect. The pre-stimulation MEP amplitudes of the stimulation group participants were used as a baseline condition for the model.

Approximations of the degrees of freedom for the fixed effects were obtained with Satterthwaite approximation using the lmerTest package [13] following Luke’s recommendation [14]. The main effects were assessed by Wald Chi-squared tests. Considering that the main effect of the factors and their interaction were significаnt, estimаted mаrginаl meаns (EMMs) of pаirwise compаrisons were acquired for post hoc testing using emmeans package for R. The resulting p-values of the pairwise comparisons were corrected concerning the fаlse discovery rаte аccording to Benjаmini аnd Hochberg аdjustment [15].

RESULTS

Effects of the tsDCS on MEP amplitudes

The significance of the main effects (group and time) and interactions within the linear mixed-effects model were examined. In turn, neither the group factor (F(2, 76)=1.67, p=0.19) nor the time factor (F(2, 4655)=0.99, p=0.37) explained the data significantly. However, the effect of their interaction (F(4, 4655)=5.57, p <0.001) was significant. Specifically, the linear mixed model fit of the MEP amplitudes recorded before (T_before), immediately after (T₀), and with a 15-min delay after the stimulation or sham session (T₁₅) was performed with restricted maximum likelihood criterion at convergence of 26554.5.

A set of pairwise comparisons was also performed between EMMs between sets of MEP aptitudes within 1 day, which showed no significant deviation from the baseline condition for all the pairwise comparisons (Fig. 1).

Fig. 1. MEP (motorevoked potentials) amplitudes normalized by prestimulation (T_before) values for groups receiving tsDSC and sham stimulation. The MEPs are recorded immediately after the stimulation (T₀) and within a 15-min delay (T₁₅). Error bars represent 95% CI of the estimates (ns, not significant).

Рис. 1. Амплитуды MEP, нормализованные по значениям до стимуляции (T_before) для групп, получавших tsDSC и плацебо-стимуляцию. MEP регистрируют сразу после стимуляции (Т₀) и с 15-минутной задержкой (Т₁₅). Столбики погрешностей представляют собой 95% доверительный интервал оценок; ns — не имеет статистической значимости.

Effect of tsDCS on the development of new motor skills in healthy participants

The effects of tsDCS stimulation on the development of new motor skills were assessed using the 9-HPT and SRT. The results of the analysis of variance modeling showed that participants spent significantly less time finishing both motor tasks on the first day of the experimental session regardless of their group (Fig. 2).

Fig. 2. Performance timing of participants receiving anodal tsDSC and sham stimulation assessed separately for the nine-hole peg test (9-HPT) and the serial reaction time task (SRT). No significance was observed for the group factor indicated by the special symbols between bars (ns, p >0.05, not significant). The special symbols between groups of bars indicate the significance of the day factor in the two ANOVA models; ** p <0.01; ***p <0.001).

Рис. 2. Время выполнения участников, получавших анодную (tsDSC) и плацебо-стимуляцию, оценивали отдельно для теста с девятью отверстиями (9-HPT) и для задания на время последовательной реакции (SRT). Для фактора группы, обозначенного специальными символами между столбцами, значимости не наблюдалось (ns, p >0,05; статистически не значимо). Специальные символы между группами столбцов указывают на значимость фактора Day в двух моделях ANOVA; ** p <0,01; *** p <0,001.

Specifically, for the 9-HPT, the group factor did not explain the variance in the data significantly (F(2,39)=0.083, p=0.92), as well as the group x day interaction (F(2,39)=0.682, p=0.51), whereas the effect of the day factor was significant (F(1,39)=46.98, p <10⁻⁷).

Similarly, for the SRT, the group factor did not explain the variance in the data significantly (F(2,37)=1.510, p=0.23), as well as the group x day interaction (F(2,37)=1.711, p=0.19), whereas the effect of the day factor was significant (F(1,37)=24.00, p <10⁻⁴).

DISCUSSION

In this study, we estimated the effect of tsDCS on CSS excitability and the development of fine motor skills in healthy people. This study showed that the use of 11-min anodal tsDCS at the C7–Th1 level with a current of 2.5 mA did not affect changes in CSS excitability. The amplitude of the TMS-induced MEPs did not change after stimulation and 15 min after stimulation, which was confirmed statistically.

In this study, tsDCS at the level of cervical enlargement cannot induce a change in MEP amplitudes. Our findings are consistent with some previous observations. Dongés and D’Amico demonstrated that applying a 20-min cervical tsDCS at 3 mA using an anterior–posterior electrode configuration did not alter the response of upper limb muscles to TMS. This may indicate that cervical tsDCS using this set of stimulation parameters does not change corticospinal conduction at different levels (cortical and spinal) [10]. However, Lim and Shin reported that cervical tsDCS (2 mA, 20 min at C7, anterior–posterior configuration) increased CSS excitability regardless of the polarity and that excitability remained high up to 2 h after stimulation [9].

The stimulation effect is probably susceptible to the exact parameters of the stimulation protocol. The neuromodulatory effects of tsDCS may result from local variations in the current density and induced electric field along neurons, resulting in specific polarizing effects on the transmembrane potential, with axon terminals identified as the dominant cellular target [16]. These divergences are affected by various stimulation parameters, such as the electrode placement and geometry or the injected current intensity and polarity in the tsDCS protocol [17–19].

Moreover, this study shows that anodal tsDCS with such a set of parameters does not affect the production of motor skills. The participant’s ability to coordinate fingers and manipulate objects effectively (a measure of dexterity) in the 9-HPT and to produce fine movements in the SRT did not differ from the sham stimulation. Our results show that MEP amplitudes do not change either after stimulation or after 15 min. Perhaps, there was no correction of motor skills because the stimulation did not affect the CSS. In addition, stimulation acts not only on the CSS but also on other spinal tracts; for example, it can affect the lemniscal tract [20, 21] or the spinothalamic tract [22], which has previously been studied.

The mechanisms underlying tsDCS-induced plastic changes in the spinal cord are ambiguous; however, we can assume that tsDCS can affect the conduction properties of the CSS [9].

Another possibility is that tsDCS influences neuronal activity in the ascending spinal tracts, ultimately modulating excitability in their cortical targets, including motor areas. The possible support for a cortical mechanism comes from a report that noninvasive spinal stimulation appears to modulate intracortical facilitation [23].

Overall, our data support the conclusion that tsDCS with a current of 2.5 mA did not affect changes in CSS excitability. We also hypothesized that the spinal cord may act as a “pipeline” to transmit tsDCS-induced changes to the brain, thereby inducing suprasegmental effects on the brain and brainstem. The effects of tsDCS may have arisen, for example, owing to the influence of the electric field on impulse conduction, membrane excitability, and transmission of γ-aminobutyric acid GABAergic and glutamatergic [24]. We also hypothesized that using tsDCS with our parameters may have different effects on the motor skill development of people with movement disorders, and further studies are needed to confirm this assumption. Having more information about the underlying mechanisms is an important prerequisite for developing future clinical protocols and understanding how tsDCS affects the CSS. Whatever the mechanisms, by modulating spinal cord function, tsDCS could provide a future therapeutic tool to complement drugs and invasive spinal cord stimulation in the treatment of pathological conditions, including pain, spasticity, and movement disorders.

CONCLUSION

Therefore, the application of an 11-min anodal tsDCS at the C7–Th1 level with a current of 2.5 mA does not affect the amplitudes of the TMS-induced motorevoked potentials of FDI muscles. In addition, the application of anodic tsDCS at the level of the upper spinal cord segments (C7–Th1) for 11 min at 2.5 mA did not affect the motor skills in healthy people based on the nine-hole peg test and serial reaction time task.

ADDITIONAL INFORMATION

Funding source. The studies were carried out using the Unique Scientific Installation of the National Research University Higher School of Economics, “Automated System for Non-Invasive Brain Stimulation with the Possibility of Synchronous Registration of Brain Biocurrents and Eye Movement Tracking”; with the financial support of the Ministry of Science and Higher Education of the Russian Federation, grant N 075-15-2021-673.

Competing interests. The authors declare the absence of obvious and potential conflicts of interest related to the publication of this article.

Authors’ contribution. E.D. Pomelova — data collection, search for subjects, development of a protocol, analysis of literary sources, writing a text; A.V. Popyvanova — collecting data, searching for subjects, editing the article; D.O. Bredikhin — data analysis, image preparation. M.M. Koryakina — writing the text, editing the article; A.N. Shestakova — development of the protocol. E.D. Blagoveshchensky — literature analysis, data analysis, development of study protocols. All authors confirm that their authorship complies with the international ICMJE criteria (all authors made a significant contribution to the development of the concept, research and preparation of the article, read and approved the final version before publication).

ДОПОЛНИТЕЛЬНО

Источник финансирования. Исследования были проведены с использованием уникальной научной установки НИУ ВШЭ «Автоматизированная система неинвазивной стимуляции мозга с возможностью синхронной регистрации биотоков мозга и отслеживания глазодвижения»; при финансовой поддержке Министерства науки и высшего образования Российской Федерации, грант № 075-15-2021-673.

Конфликт интересов. Авторы декларируют отсутствие явных и потенциальных конфликтов интересов, связанных с публикацией настоящей статьи.

Вклад авторов. Е.Д. Помелова — сбор данных, поиск испытуемых, разработка протокола, анализ литературных источников, написание текста; А.В. Попыванова — сбор данных, поиск испытуемых, редактирование статьи; Д.О. Бредихин — анализ данных, подготовка изображений; М. М. Корякина — написание текста, редактирование статьи. А.Н. Шестакова — разработка протокола; Е.Д. Благовещенский — анализ литературы, анализ данных, разработка протоколов исследования. Все авторы подтверждают соответствие своего авторства международным критериям ICMJE (все авторы внесли существенный вклад в разработку концепции, проведение исследования и подготовку статьи, прочли и одобрили финальную версию перед публикацией).