No effect of anodal tDCS on motor cortical excitability and no evidence for responders in a large double-blind placebo-controlled trial

Background: Transcranial direct current stimulation (tDCS) has emerged as a non-invasive brain stimulation technique. Most studies show that anodal tDCS increases cortical excitability. However, this effect has been found to be highly variable. Objective: To test the effect of anodal tDCS on cortical excitability and the interaction effect of two participant-specific factors that may explain individual differences in sensitivity to anodal tDCS: the Brain Derived Neurotrophic Factor Val66Met polymorphism (BDNF genotype) and the latency difference between anterior-posterior and lateromedial TMS pulses (APLM latency). Methods: In 62 healthy participants, cortical excitability over the left motor cortex was measured before and after anodal tDCS at 2 mA for 20 min in a pre-registered, double-blind, randomized, placebo-controlled trial with repeated measures. Results: We did not find a main effect of anodal tDCS, nor an interaction effect of the participant-specific predictors. Moreover, further analyses did not provide evidence for the existence of responders and non-responders. Conclusion: This study indicates that anodal tDCS at 2 mA for 20 min may not reliably affect cortical excitability

Manifold-Topology from K-Causal Order

To a significant extent, the metrical and topological properties of spacetime can be described purely order-theoretically. The $K^+$ relation has proven to be useful for this purpose, and one could wonder whether it could serve as the primary causal order from which everything else would follow. In that direction, we prove, by defining a suitable order-theoretic boundary of $K^+(p)$, that in a $K$-causal spacetime, the manifold-topology can be recovered from $K^+$. We also state a conjecture on how the chronological relation $I^+$ could be defined directly in terms of $K^+$.Comment: v2: 9 pages, 2 figures. Minor change

TMS motor mapping: Comparing the absolute reliability of digital reconstruction methods to the golden standard

Background: Changes in transcranial magnetic stimulation motor map parameters can be used to quantify plasticity in the human motor cortex. The golden standard uses a counting analysis of motor evoked potentials (MEPs) acquired with a predefined grid. Recently, digital reconstruction methods have been proposed, allowing MEPs to be acquired with a faster pseudorandom procedure. However, the reliability of these reconstruction methods has never been compared to the golden standard. Objective: To compare the absolute reliability of the reconstruction methods with the golden standard. Methods: In 21 healthy subjects, both grid and pseudorandom acquisition were performed twice on the first day and once on the second day. The standard error of measurement was calculated for the counting analysis and the digital reconstructions. Results: The standard error of measurement was at least equal using digital reconstructions. Conclusion: Pseudorandom acquisition and digital reconstruction can be used in intervention studies without sacrificing reliability

Cerebellar transcranial direct current stimulation interacts with BDNF Val66Met in motor learning

Background: Cerebellar transcranial direct current stimulation has been reported to enhance motor associative learning and motor adaptation, holding promise for clinical application in patients with movement disorders. However, behavioral benefits from cerebellar tDCS have been inconsistent. Objective: Identifying determinants of treatment success is necessary. BDNF Val66Met is a candidate determinant, because the polymorphism is associated with motor skill learning and BDNF is thought to mediate tDCS effects. Methods: We undertook two cerebellar tDCS studies in subjects genotyped for BDNF Val66Met. Subjects performed an eyeblink conditioning task and received sham, anodal or cathodal tDCS (N = 117, between-subjects design) or a vestibulo-ocular reflex adaptation task and received sham and anodal tDCS (N = 51 subjects, within-subjects design). Performance was quantified as a learning parameter from 0 to 100%. We investigated (1) the distribution of the learning parameter with mixture modeling presented as the mean (M), standard deviation (S) and proportion (P) of the groups, and (2) the role of BDNF Val66Met and cerebellar tDCS using linear regression presented as the regression coefficients (B) and odds ratios (OR) with equally-tailed intervals (ETIs). Results: For the eyeblink conditioning task, we found distinct groups of learners (MLearner = 67.2%; SLearner = 14.7%; PLearner = 61.6%) and non-learners (MNon-learner = 14.2%; SNon-learner = 8.0%; PNon-learner = 38.4%). Carriers of the BDNF Val66Met polymorphism were more likely to be learners (OR = 2.7 [1.2 6.2]). Within the group of learners, anodal tDCS supported eyeblink conditioning in BDNF Val66Met non-carriers (B = 11.9% 95%ETI = [0.8 23.0]%), but not in carriers (B = 1.0% 95%ETI = [-10.2 12.1]%). For the vestibulo-ocular reflex adaptation task, we found no effect of BDNF Val66Met (B = −2.0% 95%ETI = [-8.7 4.7]%) or anodal tDCS in either carriers (B = 3.4% 95%ETI = [-3.2 9.5]%) or non-carriers (B = 0.6% 95%ETI = [-3.4 4.8]%). Finally, we performed additional saccade and visuomotor adaptation experiments (N = 72) to investigate the general role of BDNF Val66Met in cerebellum-dependent learning and found no difference between carriers and non-carriers for both saccade (B = 1.0% 95%ETI = [-8.6 10.6]%) and visuomotor adaptation (B = 2.7% 95%ETI = [-2.5 7.9]%). Conclusions: The specific role for BDNF Val66Met in eyeblink conditioning, but not vestibulo-ocular reflex adaptation, saccade adaptation or visuomotor adaptation could be related to dominance of the role of simple spike suppression of cerebellar Purkinje cells with a high baseline firing frequency in eyeblink conditioning. Susceptibility of non-carriers to anodal tDCS in eyeblink conditioning might be explained by a relatively larger effect of tDCS-induced subthreshold depolarization in this group, which might increase the spontaneous firing frequency up to the level of that of the carriers