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Objective To systematically review how patient characteristics and/or transcranial direct current stimulation (tDCS) parameters influence tDCS effectiveness in respect to upper limb function post-stroke. Methods Three electronic databases were searched for sham-controlled randomised trials using the Fugl-Meyer Assessment for upper extremity as outcome measure. A meta-analysis and nine subgroup-analyses were performed to identify which tDCS parameters yielded the greatest impact on upper limb function recovery in stroke patients. Results Eighteen high-quality studies (507 patients) were included. tDCS applied in a chronic stage yields greater results than tDCS applied in a (sub)acute stage. Additionally, patients with low baseline upper limb impairments seem to benefit more from tDCS than those with high baseline impairments. Regarding tDCS configuration, all stimulation types led to a significant improvement, but only tDCS applied during therapy, and not before therapy, yielded significant results. A positive dose–response relationship was identified for current/charge density and stimulation duration, but not for number of sessions. Conclusion Our results demonstrate that tDCS improves upper limb function post-stroke. However, its effectiveness depends on numerous factors. Especially chronic stroke patients improved, which is promising as they are typically least amenable to recovery. Significance The current work highlights the importance of several patient-related and protocol-related factors regarding tDCS effectiveness.

Few studies have identified the intrahemispheric functional connectivity between the ipsilateral dorsal premotor cortex (PMd) and the primary motor hand area (M1hand) due to technical limitations. In this proof-of-concept study, a novel neuronavigated dsTMS set-up was employed, combining stimulation over left PMd and left M1hand using the edge of a butterfly coil and a small cooled-coil. This arrangement was warranted because coil (over)heating and inter coil distance are limiting factors when investigating connectivity between stimulation targets in close proximity and over a longer duration. The proposed set-up was designed to deal with these limitations. Specifically, the effect of four dual-site transcranial magnetic stimulation (dsTMS) protocols on twenty-eight right-handed participants (12 males) was evaluated. These protocols differed in stimulus order, interstimulus interval and current direction induced in PMd. A structural scan with electric (E-)field modeling was obtained from seven participants prior to dsTMS, demonstrating that PMd and M1hand were effectively stimulated. Results indicate that one protocol, in which a latero-medial current was induced in PMd 2.8 ms prior to stimulation over M1hand, induced a sex-mediated effect. In males, significant inhibition of motor-evoked potentials was identified, whereas females demonstrated a facilitatory effect that did not survive correction for multiple comparisons. E-field simulations revealed that the E-field induced by the coil targeting PMd was maximal in PMd, with weaker E-field strengths extending to regions beyond PMd. Summarizing, the current dsTMS set-up enabled stimulating at an inter-target distance of 35 mm without any indications of coil-overheating.

Background: Cognitive, and motor performance are reduced in aging, especially with respect to acquisition of new knowledge, which is associated with a neural plasticity decline. Animal models show a reduction of long-term potentiation, but not long-term depression, in higher age. Findings in humans are more heterogeneous, with some studies showing respective deficits, but others not, or mixed results, for plasticity induced by non-invasive brain stimulation. One reason for these heterogeneous results might be the inclusion of different age ranges in these studies. In addition, a systematic detailed comparison of the age-dependency of neural plasticity in humans is lacking so far. Objective: We aimed to explore age-dependent plasticity alterations in adults systematically by discerning between younger and older participants in our study. Methods: We recruited three different age groups (Young: 18-30, Pre-Elderly: 50-65, and Elderly: 66 -80 years). Anodal, cathodal, or sham transcranial direct current stimulation (tDCS) was applied over the primary motor cortex with 1 mA for 15 min to induce neuroplasticity. Cortical excitability was monitored by single-pulse transcranial magnetic stimulation as an index of plasticity. Results: For anodal tDCS, the results show a significant excitability enhancement, as compared to sham stimulation, for both, Young and the Pre-Elderly groups, while no LTP-like plasticity was obtained in the Elderly group by the applied stimulation protocol. Cathodal tDCS induced significant excitability-diminishing plasticity in all age groups. Conclusion: Our study provides further insight in age-related differences of plasticity in healthy humans, which are similar to those obtained in animal models. The decline of LTP-like plasticity in higher age could contribute to cognitive deficits observed in aging. (C) 2020 The Author(s). Published by Elsevier Inc. This work was supported by a research grant from the German Federal Ministry of Education and Research (BMBF) (GCBS grant 01EE1501, TRAINSTIM grant 01GQ1424E). We thank Nicole Ruck and Eva Strzelec for their help in recruiting elderly participants. Nitsche, MA (corresponding author), Leibniz Res Ctr Working Environm & Human Factors, Dept Psychol & Neurosci, Dortmund, Germany. nitsche@ifado.de

uptake after tDCS in the bilateral precentral gyri, the bilateral postcentral gyri, the left cingulate, and the left SMA (p(FWE) < 0.028). These results suggest that perceptions of fatigue and QoL, but not objective performance fatigability, play a prominent role in Post-COVID-19-Fatigue and that tDCS might alter cerebral FDG uptake in fatigue-related brain regions in these patients. Abstract A randomized interventional cross-over trial with transcutaneous auric-ular vagus nerve stimulation (tVNS) was performed on 13 adult Systemic sclerosis (SSc) patients with chronic moderate-to-severe pain from the Scleroderma Unit of Policlinico Hospital in Milan. Patients were randomly assigned to the interventional group with tVNS (25 Hz) or to the control group based on sham stimulation (1 Hz) for 4 not consecutively hours/day for one month. Each group shifted to the opposite arm after a 4-weeks wash-out period. Pain was assessed by Numeric Rating Scale (NRS) and 10-minute ECG was recorded at rest before and after real tVNS and sham. Symbolic Heart Rate Variability (HRV) analysis was performed on ECG to assess the cardiovascular autonomic control. ANCOVA test correcting for baseline values, age, disease duration and month of treatment was used to evaluate NRS or HRV changes after tVNS and sham stimulation. For HRV statistical analysis, cardiac ejection fraction and systolic pulmonary artery pressure were also included as covariates. A linear regression model, correcting for covariates as described above, was performed to evaluate the occurrence of minimal clinically important difference (at least 2 points on NRS). Partial correlation analysis was used to estimate the relationship between NRS and HRV changes after correction for covariates. Statistical analysis showed a significant improvement of NRS score after tVNS with an estimated reduction of 2.051 NRS points (p

Recent transcranial magnetic stimulation (TMS) research indicated that the ability of the dorsolateral prefrontal cortex (DLPFC) to disinhibit the contralateral primary motor cortex (M1) during motor preparation is an important predictor for bimanual motor performance in both young and older healthy adults. However, this DLPFC-M1 disinhibition is reduced in older adults. Here, we transiently suppressed left DLPFC using repetitive TMS (rTMS) during a cyclical bimanual task and investigated the effect of left DLPFC suppression: (1) on the projection from left DLPFC to the contralateral M1; and (2) on motor performance in 21 young (mean age ± SD = 21.57 ± 1.83) and 20 older (mean age ± SD = 69.05 ± 4.48) healthy adults. As predicted, without rTMS, older adults showed compromised DLPFC-M1 disinhibition as compared to younger adults and less preparatory DLPFC-M1 disinhibition was related to less accurate performance, irrespective of age. Notably, rTMS-induced DLPFC suppression restored DLPFC-M1 disinhibition in older adults and improved performance accuracy right after the local suppression in both age groups. However, the rTMS-induced gain in disinhibition was not correlated with the gain in performance. In sum, this novel rTMS approach advanced our mechanistic understanding of how left DLPFC regulates right M1 and allowed us to establish the causal role of left DLPFC in bimanual coordination. FUNDING This work was supported by the Hercules fund AUHL/11/01 (R-3987) awarded to RM, the Internal Research Fund KU Leuven (C16/15/070), the Research Foundation Flanders (Fonds Wetenschappelijk Onderzoek; FWO) grant (G089818N) and Excellence of Science grant (EOS 30446199, MEMODYN) awarded to SS and colleagues. ACKNOWLEDGMENTS We are thankful to R. Clerckx for his support in programming the bimanual tracking task and for his help in preprocessing the acquired task data. We additionally thank E. Ghasemian Shivran and several master students of KU Leuven and UHasselt who assisted with data collection. Helpful comments on the latest version of the manuscript were given by S. Depestele.

Background: Burnout is characterized by deficiencies in attention and several components of the working memory. It has been shown that cognitive behavioral therapy can have a positive effect on burnout and depressive symptoms, however, the lingering effects of impaired attention and executive functions are the most frustrating. We hypothesized that anodal transcranial direct current stimulation (atDCS) over the left dorsolateral prefrontal cortex (DLPFC) can improve the executive control of attention and possibly several other components of working memory in patients with burnout. Methods: This was a randomized double-blind sham-controlled pilot study with two groups. Patients with burnout received three weeks of daily sessions (15 sessions in total) of atDCS or sham stimulation in addition to three weekly sessions of standard behavioral therapy. The primary outcome measure was attention and the central executive of the working memory. Secondary, the effect of atDCS was measured on other components of working memory, on burnout and depression scores, and on quality of life (QoL). Results: We enrolled and randomly assigned 16 patients to a sham or real stimulation group, 15 (7 sham, 8 real) were included in the analysis. atDCS had a significant impact on attention. Post-hoc comparisons also revealed a trend towards more improvement after real tDCS for inhibition and shifting, updating and control, and encoding. Both groups improved on burnout and depression scores. Conclusion: These data provide preliminary evidence for the value of atDCS over the left DLPFC in rehabilitating attention deficits, and possibly also central executive and encoding deficits, in burnout. However, the current study has some limitations, including the sample size and heterogeneous patient population. More elaborate studies are needed to elucidate the specific impact of atDCS over the left DLPFC on burnout. Trial registration: ISRCTN.com ( ISRCTN94275121) 17/11/19

It has been argued that age-related changes in the neurochemical and neurophysiological properties of the GABAergic system may underlie increases in reaction time (RT) in older adults. However, the role of GABA levels within the sensorimotor cortices (SMC) in mediating interhemispheric interactions (IHi) during the processing stage of a fast motor response, as well as how both properties explain interindividual differences in RT, are not yet fully understood. In this study, edited magnetic resonance spectroscopy (MRS) was combined with dual-site transcranial magnetic stimulation (dsTMS) for probing GABA+ levels in bilateral SMC and task-related neurophysiological modulations in corticospinal excitability (CSE), and primary motor cortex (M1)-M1 and dorsal premotor cortex (PMd)-M1 IHi, respectively. Both CSE and IHi were assessed during the preparatory and premotor period of a delayed choice RT task. Data were collected from 25 young (aged 18-33 years) and 28 older (aged 60-74 years) healthy adults. Our results demonstrated that older as compared to younger adults exhibited a reduced bilateral CSE suppression, as well as a reduced magnitude of long latency M1-M1 and PMd-M1 disinhibition during the preparatory period, irrespective of the direction of the IHi. Importantly, in older adults, the GABA+ levels in bilateral SMC partially accounted for task-related neurophysiological modulations as well as individual differences in RT. In contrast, in young adults, neither task-related neurophysiological modulations, nor individual differences in RT were associated with SMC GABA+ levels. In conclusion, this study contributes to a comprehensive initial understanding of how age-related differences in neurochemical properties and neurophysiological processes are related to increases in RT. ispartof: NEUROIMAGE vol:243 ispartof: location:United States status: published

The role of the dorsolateral prefrontal cortex (DLPFC) in the regulation of bimanual coordination appears to become crucial with aging. Age-related changes in the involvement of the DLPFC in bimanual coordination were studied by using disruptive repetitive TMS (rTMS), inducing a transient lesion in this brain structure. Neurophysiological as well as behavioral effects of suppressing DLPFC during the preparation and execution of a bimanual task were studied in 41 healthy adults (young and old). Specifically, we combined short-train rTMS with single pulse TMS to examine the effect of DLPFC suppression on the interhemispheric projection to the contralateral primary motor cortex (M1) during motor preparation. Findings revealed that compromised interhemispheric DLPFC-M1 disinhibition during motor preparation in older adults resulted in less accurate bimanual performance. The altered DLPFC-M1 interaction in older adults appeared to result from a decline in local inhibitory mechanisms in the DLPFC. In addition, the induction of DLPFC suppression affected task accuracy, but not movement stability in both age groups. Taken together, these results suggest that DLPFC acts as a key regulator in the control of bimanual movement coordination.

Introduction Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain. Previous literature revealed a decline in GABA concentration in frontal and parietal regions as a result of age (Gao et al., 2013; Porges et al., 2017). Nevertheless, it is not clear whether this age-related decline in GABA concentration is specific to these regions or a widespread effect. Therefore, we aimed to investigate age-related changes in GABA concentrations within several cortical and subcortical regions. Since regional GABA concentration has been found to be correlated with various behavioral measures (Puts & Edden, 2012; Stagg, 2014), insight into the effect of healthy aging on brain chemistry may increase our understanding of the underlying neural mechanisms that contribute to cognitive and motor deficits in older adults. Methods A total of 30 healthy right-handed young (14 men, mean age = 23.2) and 29 healthy right-handed older adults (13 men, mean age = 67.5) participated in this study. GABA+ concentrations were acquired in nine different voxels using the MEGA-PRESS spectral editing method on a Philips 3T Achieva Magnetic Resonance scanner (Philips Healthcare, The Netherlands) with a 32 channel receiver head coil. The following acquisition parameters were used: 14 ms editing pulses at 7.5 ppm (edit-OFF) and 1.9 ppm (edit-ON), TE = 68 ms, TR = 2 s, 320 averages, 2 kHz spectral width, MOIST water suppression. Voxels of interest were bilateral primary motor cortex (3x3x3cm³), bilateral dorsal premotor cortex (4x2.5x2.5cm³), bilateral striatum (3x3x3cm³), presupplementary motor area (3x3x3cm³), right inferior frontal cortex (4x2.5x2.5cm³) and occipital cortex (3x3x3cm³). Additionally, a T1 scan was acquired in order to calculate the cerebrospinal fluid (CSF) fraction of each voxel. The obtained MRS spectra were analyzed using the Gannet software toolkit (Edden, Puts, Harris, Barker, & Evans, 2013) and GABA+ concentrations were calculated relative to water. Differences in GABA+ concentrations between young and older adults were tested with a mixed model with age group and voxel as fixed factor, participant as random factor and CSF as covariate (JMP Pro 12). Significant interaction effects were further investigated using unpaired student’s t-tests with Bonferroni correction. Results Older adults had lower GABA+ concentrations in all voxels in comparison with young adults (Figure 1). Statistical analysis however indicated that there was no effect of age on GABA+ concentrations (F1,106.4 = 0.317, p = .574), but there was an interaction between age and voxel (F8, 404.8 = 2.009, p = .0442). Between-group post hoc analysis showed lower GABA+ concentrations within right striatum in older adults compared to young adults (t = -2.86, p = .0045). GABA+ concentrations did not significantly differ between young and older adults in all other voxels (all p ≥ .1604). Conclusions In the present study, we found a decline in GABA+ concentrations with age, however, this decline was only present within right striatum. Within bilateral primary motor cortex, bilateral dorsal premotor cortex, left striatum, presupplementary motor area, right inferior frontal cortex and occipital cortex, the decline in GABA+ concentrations was not significant. This suggests that biochemical changes as a result of healthy aging are not uniform across the human brain. However, it is possible that the regional concentration of macromolecules (i.e. part of the edited GABA+ signal) changes as a function of age, thereby masking the decline in GABA concentrations.