No abstract

Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.

Function-guided navigation is commonly used when assessing cortical excitability using transcranial magnetic stimulation (TMS). However, the required accuracy, stability and the effect of a change in coil positioning are not entirely known. This study investigates the accuracy of function-guided navigation for determining the hotspot. Furthermore, it evaluates the effect of a change in coil location on the single and paired pulse excitability measures: motor evoked potential (MEP) amplitude, TMS evoked potential (TEP) and long intracortical inhibition (LICI), and of a change in coil orientation on LICI. Eight healthy subjects participated in the single pulse study, and ten in the paired pulse study. A robot-guided navigation system was used to ensure accurate and stable coil positioning at the motor hotspot as determined using function-guided navigation. In addition, we targeted four locations at 2 mm and four at 5 mm distance around the initially defined hotspot, and we increased and decreased the coil orientation by 10°. In none of the subjects, the largest MEP amplitudes were evoked at the originally determined hotspot, resulting in a poor accuracy of function-guided navigation. At the group level, a change in coil location had no significant effect on the MEP amplitude, TEP, or LICI, and a change in coil orientation did not significantly affected LICI. However, at the subject level significant effects on MEP amplitude, TEP, and LICI were found for changes in coil location or orientation, although absolute differences were relatively small and did not show a consistent pattern. This study indicates that a high accuracy in coil positioning is especially required to measure cortical excitability reliably in individual subjects using single or paired pulse TMS.Electronic supplementary materialThe online version of this article (10.1007/s10548-018-0655-6) contains supplementary material, which is available to authorized users.

TAK-653 is a novel α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1–50 mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6 mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.

Humans show a variation in physiological processes during the day. To reliably assess (changes in) cortical excitability with transcranial magnetic stimulation (TMS), it is relevant to know the natural variation in TMS readouts during the day. In case of significant daytime variations, this should be taken into account when scheduling (follow-up) measurements. This study aims to evaluate the influence of the time of day on the resting motor threshold (RMT), motor evoked potential (MEP) and TMS evoked potential (TEP) in healthy controls. TMS-EMG-EEG was recorded in 16 healthy subjects. At both motor cortices, we administered 75 pulses at an intensity of 110% RMT. Subjects were stimulated during five sessions in one day (8:00 AM, 10:30 AM, 1:00 PM, 3:30 PM and 6:00 PM) while keeping the stimulation intensity constant. We compared the TEP waveforms between the five sessions with a cluster-based permutation analysis, and the RMT and MEP amplitude with rmANOVA. In general there were no significant differences between the five sessions in the RMT, MEP amplitude or TEP. Only for the left side, N100 amplitude was larger at 3:30 PM than 10:30 AM. The standard deviation of the P30 and N100 amplitude was significantly higher between subjects within one session than within single subjects during the day. The TEP is highly reproducible during the day, with a low intra-individual variation compared to the inter-individual variation. In addition, we found no significant variation of the RMT and MEP amplitude between multiple sessions on one day.

Long non-coding RNA (lncRNA) genes are known to have diverse impacts on gene regulation. However, it is still a major challenge to distinguish functional lncRNAs from those that are byproducts of surrounding transcriptional activity. To systematically identify hallmarks of biological function, we used the GTEx v8 data to profile the expression, regulation, network relationships and trait associations of lncRNA genes across 49 tissues encompassing 87 distinct traits. In addition to revealing widespread differences in regulatory patterns between lncRNA and protein-coding genes, we identified novel disease-associated lncRNAs, such as C6orf3 for psoriasis and LINC01475/RP11-129J12.1 for ulcerative colitis. This work provides a comprehensive resource to interrogate lncRNA genes of interest and annotate cell type and human trait relevance.One Sentence SummarylncRNA genes have distinctive regulatory patterns and unique trait associations compared to protein-coding genes.

No abstract

For physiological brain function a particular balance between excitation and inhibition is essential. Paired pulse transcranial magnetic stimulation (TMS) can estimate cortical excitability and the relative contribution of inhibitory and excitatory networks. Combining TMS with electroencephalography (EEG) enables additional assessment of the spatiotemporal dynamics of neuronal responses in the stimulated brain. This study aims to evaluate the spatiotemporal dynamics and stability of single and paired pulse TMS-EEG responses, and assess long intracortical inhibition (LICI) at the cortical level. Twenty-five healthy subjects were studied twice, approximately one week apart. Manual coil positioning was applied in sixteen subjects and robot-guided positioning in nine. Both motor cortices were stimulated with 50 single pulses and 50 paired pulses at each of the five interstimulus intervals (ISIs): 100, 150, 200, 250 and 300 ms. To assess stability and LICI, the intraclass correlation coefficient and cluster-based permutation analysis were used. We found great resemblance in the topographical distribution of the characteristic TMS-EEG components for single and paired pulse TMS. Stimulation of the dominant and non-dominant hemisphere resulted in a mirrored spatiotemporal dynamics. No significant effect on the TMS-EEG responses was found for either stimulated hemisphere, time or coil positioning method, indicating the stability of both single and paired pulse TMS-EEG responses. For all ISIs, LICI was characterized by significant suppression of the late N100 and P180 components in the central areas, without affecting the early P30, N45 and P60 components. These observations in healthy subjects can serve as reference values for future neuropsychiatric and pharmacological studies.