It has been proposed that the effectiveness of non-invasive brain stimulation (NIBS) as a cognitive enhancement technique may be enhanced by combining the stimulation with concurrent cognitive activity. However, the benefits of such a combination in comparison to protocols without ongoing cognitive activity have not yet been studied. In the present study, we investigate the effects of fMRI-guided high-frequency repetitive transcranial magnetic stimulation (HF rTMS) over the left dorsolateral prefrontal cortex (DLPFC) on working memory (WM) in healthy volunteers, using an n-back task with spatial and verbal stimuli and a spatial span task. In two combined protocols (TMS + WM + (maintenance) and TMS + WM + (rest)) trains of stimuli were applied in the maintenance and rest periods of the modified Sternberg task, respectively. We compared them to HF rTMS without a cognitive load (TMS + WM −) and control stimulation (TMS − WM + (maintenance)). No serious adverse effects appeared in this study. Among all protocols, significant effects on WM were shown only for the TMS + WM − with oppositely directed influences of this protocol on storage and manipulation in spatial WM. Moreover, there was a significant difference between the effects of TMS + WM − and TMS + WM + (maintenance), suggesting that simultaneous cognitive activity does not necessarily lead to an increase in TMS effects.

The use of metaplasticity-based intermittent theta-burst stimulation (iTBS) protocols including several stimulation blocks could be a possible approach to increasing stimulation effectiveness. Our aim was to investigate the neurophysiological effects of two protocols with a short and a long interval between blocks. Seventeen healthy volunteers received four protocols in a pseudorandomized order: iTBS 0-15 (two blocks of active iTBS of primary motor cortex (M1) separated by 15 min and a control stimulation block of the vertex in 60 min from the first block); iTBS 0-60 (active iTBS, a control block in 15 min, and an active block in 60 min); iTBS 0 (active iTBS and two control blocks with the same intervals); and Control (three control blocks). The motor evoked potentials (MEPs) were measured before the first and after the second and third blocks. We have shown no significant differences between the effects of the protocols on both the motor cortex excitability and the responder rates. No significant changes of MEPs were observed after all the protocols. The reliability for the responsiveness to a single block between two sessions was insignificant. Our data confirm low reproducibility of the response to iTBS and suggest that the use of repeated protocols does not increase the responder rates or neurophysiological effects of iTBS.

Cognitive impairment (CI) is a relatively common manifestation of multiple sclerosis (MS), which can occur with any type of the disease course and activity. The largest CI prevalence and severity are observed in progressive MS. In relapsing-remitting MS the most prominent deterioration of cognitive functions is seen during relapses; however, in some patients it can continue also throughout remission. In a small number of patients CI can be the most significant symptom of the disease; in addition, it sometimes can be the only clinical feature of the relapse. Despite this, in clinical practice CI remains out of the focus of attention, and is not evaluated when assessing the disease severity and/or activity, while CI is not included into EDSS. Nonetheless, a number of specialized neuropsychological tests and batteries has been developed recently, which can be used for both screening and detailed assessment of CI in MS, as well as for assessment of its changes over time. CI has a negative impact on MS patients' quality of life, their social interactions, daily and occupational activities. The influence of disease-modifying agents on CI has been poorly investigated; however, there is evidence that they can reduce the degree of CI. The optimal choice of pathogenetic treatment in patients with CI remains understudied. There is no convincing evidence of the effectiveness of symptomatic pharmacological treatment of CI in MS, and cognitive rehabilitation is the only approach with confirmed effectiveness. Considering the limitations of this technique (its availability, quite a big number of sessions), there is a need to search for other methods to increase its efficacy, including non-invasive neuromodulation (in particular, transcranial direct current stimulation or transcranial magnetic stimulation). This article is focused on a brief review of the main diagnostic methods of CI in MS, its pathogenetic and symptomatic treatment, and cognitive rehabilitation techniques, as well as on the results of the studies on non-invasive neuromodulation.

Metaplasticity (plasticity of synaptic plasticity) is defined as a change in the direction or degree of synaptic plasticity in response to preceding neuronal activity. Recent advances in brain stimulation methods have enabled us to non-invasively examine cortical metaplasticity, including research in a clinical setting. According to current knowledge, non-invasive neuromodulation affects synaptic plasticity by inducing cortical processes that are similar to long-term potentiation and depression. Two stimulation blocks are usually used to assess metaplasticity priming and testing blocks. The technology of studying metaplasticity involves assessing the influence of priming on the testing protocol effect. Several dozen studies have examined the effects of different stimulation protocols in healthy persons. They found that priming can both enhance and weaken, or even change the direction of the testing protocol effect. The interaction between priming and testing stimulation depends on many factors: the direction of their effect, duration of the stimulation blocks, and the interval between them. Non-invasive brain stimulation can be used to assess aberrant metaplasticity in nervous system diseases, in order to develop new biomarkers. Metaplasticity disorders are found in focal hand dystonia, migraine with aura, multiple sclerosis, chronic disorders of consciousness, and age-related cognitive changes. The development of new, metaplasticity-based, optimized, combined stimulation protocols appears to be highly promising for use in therapeutic neuromodulation in clinical practice.

Introduction. Cerebral small vessel disease (CSVD) is one of the leading causes of vascular and mixed cognitive impairment (CI). Treatment options for CSVD-associated CI are limited. Repetitive transcranial magnetic stimulation (rTMS) is a promising non-drug treatment option. The aim of the study was to evaluate the effects of 10 rTMS sessions of the left dorsolateral prefrontal cortex (DLPFC) on cognitive functions in CSVD patients. Materials and methods. The study included 30 patients with CSVD and moderate CI randomized to the active (DLPFC stimulation; n = 20) and control (vertex stimulation; n = 10) groups. Both groups received 10 sessions of high-frequency rTMS. The DLPFC target was selected based on the individual paradigm fMRI data with a focus on executive functions. Cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA), the Trail Making Test (TMT), the Tower of London Test, and the Rey–Osterrieth Complex Figure Test before, immediately after, and 3 months after the stimulation. Adverse events were assessed using standardized questionnaires. Results. The active group showed a significantly better effect compared to the control group according to MoCA, TMT A and B, The Tower of London Test, delayed recall on the Rey–Osterrieth Complex Figure Test immediately after the stimulation and MoCA, TMT A and B and The Tower of London 3 months after the stimulation. Adverse events in the study were mild and did not affect treatment adherence. Conclusion. rTMS is a promising, safe, and well-tolerated treatment option for mild cognitive impairment in CSVD. However, additional research is needed to make recommendations for its clinical use.

Background. Paired-pulse transcranial magnetic stimulation allows assessing intracortical inhibition. However, a high variability of motor evoked potential (MEP) amplitude is a limitation of its use. Therefore, a new threshold tracking technique became of particular interest, which is based on the measurement not of the amplitude, but of the change of test stimulus intensity required to induce a MEP of a given amplitude.Aim. The assessment of absolute and relative reliability of short-interval intracortical inhibition (SICI) using threshold tracking technique in healthy volunteers.Materials and methods. All healthy volunteers included into the study (n = 12) underwent diagnostic paired-pulse transcranial magnetic stimulation in two consecutive days. The procedure included registration of passive motor threshold; the registration of 30 MEPs with supra-threshold intensity and determination of SICI using threshold tracking technique. At the first day the procedure was performed twice (T1, T2), at the second day – once (T3). Standard error of the measurement (SEM) and SEM% were calculated to assess absolute reliability, and intra-class correlation coefficient – for the assessment of relative reliability.Results. A good or excellent relative reliability were observed for SICI averaged at intervals 1.0–3.0 ms and 1.0–7.0 ms when assessed within a day or at different days. Relative reliability of SICI at separate interstimulus intervals varied in a wide range. SEM% was more than 10 % both for averaged SICI and SICI at all interstimulus intervals. Motor threshold had excellent reliability both assessed within a day and at different days, and low SEM values (5.6 % for Т1–Т2 and 4.39 % for Т1–Т3). High SEM and SEM% were observed for average MEP amplitude, it also had a moderate relative reliability when assessed within a day and a poor one – at different days.Conclusion. Calculation of averaged SICI can be recommended in further studies because of its high reliability values.