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In recent years, there has been debate about the effectiveness of treatments from different fields, such as neurostimulation, neurofeedback, brain training, and pharmacotherapy. This debate has been fuelled by contradictory and nuanced experimental findings. Notably, the effectiveness of a given treatment is commonly evaluated by comparing the effect of the active treatment versus the placebo on human health and/or behaviour. However, this approach neglects the individual’s subjective experience of the type of treatment she or he received in establishing treatment efficacy. Here, we show that individual differences in subjective treatment - the thought of receiving the active or placebo condition during an experiment - can explain variability in outcomes better than the actual treatment. We analysed four independent datasets (N = 387 participants), including clinical patients and healthy adults from different age groups who were exposed to different neurostimulation treatments (transcranial magnetic stimulation: Studies 1 and 2; transcranial direct current stimulation: Studies 3 and 4). Our findings show that the inclusion of subjective treatment can provide a better model fit either alone or in interaction with objective treatment (defined as the condition to which participants are assigned in the experiment). These results demonstrate the significant contribution of subjective experience in explaining the variability of clinical, cognitive, and behavioural outcomes. We advocate for existing and future studies in clinical and non-clinical research to start accounting for participants’ subjective beliefs and their interplay with objective treatment when assessing the efficacy of treatments. This approach will be crucial in providing a more accurate estimation of the treatment effect and its source, allowing the development of effective and reproducible interventions.

Abstract Non-invasive brain stimulation has been suggested as a potential treatment for improving symptomology and cognitive deficits in Attention-Deficit/Hyperactivity Disorder (ADHD), the most common childhood neurodevelopmental disorder. Here, we examined whether a novel form of stimulation, high-frequency transcranial random noise stimulation (tRNS), applied with cognitive training (CT), may impact symptoms and neural oscillations in children with ADHD. We conducted a randomized, double-blind, sham-controlled trial in 23 unmedicated children with ADHD, who received either tRNS over the right inferior frontal gyrus (rIFG) and left dorsolateral prefrontal cortex (lDLPFC) or sham stimulation for 2 weeks, combined with CT. tRNS + CT yielded significant clinical improvements (reduced parent-reported ADHD rating-scale scores) following treatment, compared to the control intervention. These improvements did not change significantly at a 3-week follow-up. Moreover, resting state (RS)-EEG periodic beta bandwidth of the extracted peaks was reduced in the experimental compared to control group immediately following treatment, with further reduction at follow-up. A lower aperiodic exponent, which reflects a higher cortical excitation/inhibition (E/I) balance and has been related to cognitive improvement, was seen in the experimental compared to control group. This replicates previous tRNS findings in adults without ADHD but was significant only when using a directional hypothesis. The experimental group further exhibited longer sleep onset latencies and more wake-up times following treatment compared to the control group. No significant group differences were seen in executive functions, nor in reported adverse events. We conclude that tRNS + CT has a lasting clinical effect on ADHD symptoms and on beta activity. These results provide a preliminary direction towards a novel intervention in pediatric ADHD.

Previous research has highlighted the role of the excitation/inhibition (E/I) ratio for typical and atypical development, mental health, cognition, and learning. Other research has highlighted the benefits of high-frequency transcranial random noise stimulation (tRNS)-an excitatory form of neurostimulation-on learning. We examined the E/I as a potential mechanism and studied whether tRNS effect on learning depends on E/I as measured by the aperiodic exponent as its putative marker. In addition to manipulating E/I using tRNS, we also manipulated the level of learning (learning/overlearning) that has been shown to influence E/I. Participants (n = 102) received either sham stimulation or 20-minute tRNS over the dorsolateral prefrontal cortex (DLPFC) during a mathematical learning task. We showed that tRNS increased E/I, as reflected by the aperiodic exponent, and that lower E/I predicted greater benefit from tRNS specifically for the learning task. In contrast to previous magnetic resonance spectroscopy (MRS)-based E/I studies, we found no effect of the level of learning on E/I. A further analysis using a different data set suggest that both measures of E/I (EEG versus MRS) may reflect, at least partly, different biological mechanisms. Our results highlight the role of E/I as a marker for neurostimulation efficacy and learning. This mechanistic understanding provides better opportunities for augmented learning and personalized interventions.

Previously we found perspective taking (PT) influenced affect ratings of negative pictures more than neutral pictures. The current follow-up experiments extend that research to explore effects of perspective taking with positive valence pictures. We used stimuli consisting of neutral, happy and sad pictures. Stimuli were presented either mixed within blocks (Experiment 1) or separated by emotion (neutrals + happy/sad) into two separate blocks (Experiment 2). Participants rated (from 1‐ to 7 based on emotional strength) stimuli from different perspectives (sensitive/tough/their own, i.e., “me”). Emotional strength rating was a dependent variable. A significant interaction between valence and PT was found in both experiments. The difference between adopting sensitive and tough perspectives toward sadness was larger than toward the neutral condition, replicating our results from the previous study. The same difference (sensitive-tough) was larger toward the happiness condition than toward the neutral one (this was a trend in Experiment 1 and was significant in Experiment 2) and toward the sadness condition than toward the happy one. These results suggest that PT effects on emotional ratings are modulated by valence of stimuli.

Environmental cues can influence basic perceptual and attentional processes especially in an emotional context. In the current study, we aimed to investigate the effect of a non-emotional common environmental cue-a traffic light-on a higher cognitive operation-inhibition. In two experiments, we administered a novel version of the stop-signal task, in which the go task was to determine the color of a traffic light. In order to investigate the influence of each of the cues on inhibitory processes, separate tracking procedures (one for each cue) were applied simultaneously to the stop-signal delay. In Experiment 1, we found that reaction time in no-stop-signal trials was faster when a green traffic light was present, whereas stop-signal reaction time was longer when a red traffic light was present. In Experiment 2, neutral control cues were used in addition to a red and green light. The results indicate that the differences between red and green stem from an association between the color red and stop processes (rather than from the green-go association). These results strengthen previous findings showing the effect of environmental cues on attentional processes and go beyond them by showing that the effect is not restricted to emotional cues. Most importantly, the current study results suggest that environmental cues can also influence complex cognitive operations such as inhibitory control. These results might have specific implications for our understanding of the processes that underlie specific psychiatric disorders characterized by inhibitory deficit.

Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by outlining the effect of core promoter-dependent regulation on embryonic development and the proper function of an organism. We demonstrate in vivo the importance of the downstream core promoter element (DPE) in complex heart formation in Drosophila. Pioneering a novel approach using both CRISPR and nascent transcriptomics, we show the effects of mutating a single core promoter element within the natural context. Specifically, we targeted the downstream core promoter element (DPE) of the endogenous tin gene, encoding the Tinman transcription factor, a homologue of human NKX2-5 associated with congenital heart diseases. The 7 bp substitution mutation results in massive perturbation of the Tinman regulatory network that orchestrates dorsal musculature, which is manifested as physiological and anatomical changes in the cardiac system, impaired specific activity features, and significantly compromised viability of adult flies. Thus, a single motif can have a critical impact on embryogenesis and, in the case of DPE, functional heart formation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Previous investigation of cognitive processes using transcranial magnetic stimulation (TMS) have explored the response to different stimulation parameters such as frequency and coil location. In this study, we attempt to add another parameter by exploiting the spatial profiles of TMS coils to infer regional information concerning reward-related behavior. We used different TMS coils to modulate activity in the prefrontal cortex (PFC) and examined resulting changes in behavior and associated brain activity. More specifically, we used the Figure-8 coil to stimulate a portion of the dorsolateral PFC (DLPFC) and the H-Coil to stimulate a larger volume within the lateral PFC (LPFC). Healthy human volunteers completed behavioral questionnaires ( n  = 29) or performed a reward-related decision-making functional MRI (fMRI) task ( n  = 21) immediately before and after acute high-frequency stimulation (10 Hz) with either a Figure-8 coil, H-Coil, or a sham coil. Stimulation was found to induce behavioral changes as well as changes in brain activation in key nodes of the reward network. Right LPFC, but not right DLPFC or sham, stimulation was found to induce changes in both behavioral scores and brain activation in key nodes of the reward system. In conclusion, this study supports the role of the right LPFC in reward-related behavior and suggest that the pathways through which the observed effects were generated are located outside the area of the DLPFC that is traditionally targeted with TMS. These results demonstrate the use of TMS coils with different spatial profiles as an informative tool to investigate anatomic and functional correlates of behavior., Competing Interests: A.Z. and Y.R. are inventors of the deep transcranial magnetic stimulation (DTMS) coil systems, serve as consultant and chief engineer (respectively) for, and has financial interests in BrainsWay. G.S.P. and H.M. have financial interest in BrainsWay., (Copyright © 2023 Pell et al.)

Introduction: Uterine rupture during labor is a life-threatening event associated with high morbidity for both mother and fetus. While the immediate maternal and neonatal outcomes of uterine rupture are well established, less is known regarding the long-term respiratory morbidity of offspring which survived uterine rupture., Aim: To assess whether a history of uterine rupture at birth, is associated with an increased risk for future offspring respiratory morbidity., Materials and Methods: In this population-based retrospective cohort study, all singleton deliveries between 1991 and 2014 were included. Known offspring chromosomal or congenital anomalies and cases of perinatal mortality were excluded from the analysis. The incidence of hospitalizations with respiratory morbidities, predefined in a set of ICD-9 codes, was compared between offspring delivered with or without uterine rupture. Cox proportional hazards models were conducted, to control for each confounder separately., Results: During the study period 238,622 deliveries met the inclusion criteria, of those 127 (0.053%) were complicated by uterine rupture. Rates of respiratory related hospitalizations were 7.1 and 4.9%, among offspring delivered with or without uterine rupture, respectively ( p  = .22), and in the Kaplan- Meier survival curves, no significant differences were found between the groups (log rank test p  = .241). While using Cox proportional hazards models and controlling for each confounder separately, uterine rupture was not found to be an independent risk factor for long-term respiratory morbidity of the offspring., Conclusion: Uterine rupture was not found as an independent risk factor for offspring long-term respiratory morbidity. The limited number of cases in the exposed group, could only demonstrate a trend with no significance, and therefore further investigation is required.

Many cross-sectional studies have tried to assess the in vivo effect of oxidative stress on organismal aging in general and on telomere length dynamics specifically. Here we followed telomere length dynamics over a 12-month interval, in divers exposed to intense hyperbaric oxygen in comparison with an age-matched control group. Both groups were exposed to extreme physical activity, as well. Among the divers following the oxidative stress, significant telomere elongation was observed in granulocytes and naïve T cells, but not in memory T cells and B cells. Telomere length in granulocytes was mildly elongated in the control group as well, a finding that may relate to the extreme physical activity to which they were exposed. While telomere elongation in naïve T cells may be attributed to telomerase activation, we suggest that in granulocytes the elongation results from undifferentiated hematopoietic cells carrying longer telomeres that repopulate the peripheral hematopoietic compartment. This event might be accompanied by enhanced cell division within the repopulating pool. Since the aging of mammalian tissues can be attributed in part to the reduction in the replicative potential of self renewing cells, enhanced cell turnover under conditions of hyperbaric oxidative stress might be directly relevant to tissue and organismal aging., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)