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Design and Procedure | GIST | The study was approved by the ethics committee of the Max Planck Institute for Human Development and the University of Granada. Participants were provided with information about the frequency of benefits and side effects of 3 painkilling medications (i.e., aspirin, ibuprofen, and paracetamol) in comparison with a placebo. The clinical evidence was taken from 3 Cochrane reviews,Illustration of the stimuli: the graphical (panel A) and numerical (panel B) representation of the statistical information about the painkillers.After providing informed consent and stating demographic characteristics, participants were randomly assigned to the “no choice” or “choice” conditions and were provided with information about the medications. Within the “no choice” condition, half of the participants were randomly assigned to receive the numerical representation of the information, while the other half was randomly assigned to receive the graphical representation of the information. Within the “choice” condition, participants saw a brief example of what the numerical and graphical representation would look like and could decide which one they wanted to receive.All participants received an actual printout of the information, either as numerical or graphical representation, and were asked a series of questions about the medication with the printout directly in front of them (T1). These questions concerned comprehension of the information, subjective evaluations of perceived accessibility of the information, and subjective attractiveness ratings of the representation (see the “Measures” section for details on those and all subsequent variables). Next, participants returned the printout with the representation to the experimenter and filled out the graph literacy and numeracy scale. Then, there was a 120 min break. During this break, participants attended to a lecture and a practice exercise about a topic unrelated to the current research (healthy nutrition in adolescents). After this break, participants received a task in which they had to recall the same knowledge questions that they had answered previously but without being provided with the information (T2).In sum, the independent variables were condition (“no choice” v. “choice”), whether participants worked with the numerical or the graphical representation of the information, and their graph literacy. The dependent variables were comprehension and recall of both verbatim and gist knowledge (and we generally use the term | PMC10625725 |
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Measures | All knowledge questions as well as subjective ratings were previously used by Gaissmaier et al. | PMC10625725 |
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Gist knowledge | GIST | Gist knowledge reflects the essential understanding of the information and was assessed with 5 qualitative questions that were nonnumerical and asked for ordinal comparisons between the painkillers (e.g., “Which drug caused side effects least frequently?”“Which painkiller was worst overall?”). To answer these questions correctly, participants needed to consider the differences a medication made in comparison with a placebo group; for instance, whether side effects were more frequently observed in the medication compared with the placebo group. This placebo scoring is therefore how we scored the answers to the gist knowledge question for the main text. However, participants may have erroneously looked at only the medication condition, ignoring the placebo condition. Therefore, we also checked the results with an alternative medication-only scoring scheme and will report only its most central findings in the main text, whereas the details are reported in the | PMC10625725 |
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Verbatim knowledge | Verbatim knowledge reflects the precise quantitative understanding and was assessed with 8 quantitative questions that asked for numerical statements and comparisons. To answer those questions, participants needed to read off frequencies from the information chart (e.g., “How many patients experience side effects with Ibuprofen?”) and compute absolute differences between 2 frequencies from the information chart (e.g., “How many patients experience a benefit of ibuprofen that they would not have had with a placebo?”). The verbatim knowledge score is the average proportion of correct answers and was assessed with identical questions at T1 and T2. Missing cells were treated as mistakes. | PMC10625725 |
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Accessibility | Subjective accessibility of the information was assessed with 5 questions, each of which could be answered on a 5-point scale ranging from 1 ( | PMC10625725 |
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Attractiveness | Subjective attractiveness of the representation was assessed with 8 questions, each of which could be answered on a 5-point scale ranging from 1 ( | PMC10625725 |
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Graph literacy | We assessed graph literacy using the Spanish translation of the Graph Literacy Scale. The scale assesses an individual’s knowledge of health-related information based on graphical representations with 13 items on 3 levels of difficulty: reading the data (i.e., finding the specific information on a graph; 4 items), reading between the data (i.e., understanding relationships in the data shown in the graph; 4 items), and reading beyond the data (i.e., making inferences and predictions from the presented data; 5 items). The English and German versions of this scale were validated on nationally representative samples in Germany and the United States and showed good psychometric properties. | PMC10625725 |
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Numeracy | We assessed numeracy as a control variable, because it is correlated with graph literacy (in our sample: | PMC10625725 |
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Participants | One hundred sixty participants (80 in each of the conditions “choice” and “no choice”) were included in the study that comprised working with the materials (T1) and the recall test (T2). All participants were students at the University of Granada, Spain, and they received course credit for participation. The sample included 78 females and was | PMC10625725 |
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Results | The data and analysis script for this study are openly available at | PMC10625725 |
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Participant Characteristics | As presented in Participant Characteristics and Descriptive Statistics for Conditions “No Choice” and “Choice”This percentage is based on | PMC10625725 |
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What Is Chosen Predominantly, and Who Chose Graphs Rather than Numbers? | We first checked whether participants in the “choice” condition were more likely to choose one of the representations by comparing the actual choice proportions with a 50/50 split, using a binomial test. Participants were generally more likely to choose the graphical representation than the numerical one. Of the 80 participants in this condition, there were 50 participants (62.5%) who chose the graphical representation but only 30 (37.5%) who chose the numerical representation, which we compared to 50% each expected by chance with a binomial test, Within the “choice” condition, we then tested whether participants who chose the graphical condition had higher graph literacy and lower numeracy scores than those who chose the numerical representation, using Participant Characteristics and Descriptive Statistics of Participants Who Chose the Numerical and Graphical Representation in the “Choice” Condition ( | PMC10625725 |
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Does Choice Foster Knowledge? | GIST | To analyze whether knowledge differed between the “no choice” and the “choice” condition, we ran a linear mixed-effects model with random intercepts for participants. The outcome variable was knowledge and the predictors were time (T1 v. T2; effect-coded as T1 = −0.5, T2 = +0.5) and knowledge type (verbatim v. gist; effect coded as verbatim = −0.5, gist = +0.5), the between-subjects factors condition (“no choice” v. “choice”; effect coded as no choice = −0.5, choice = +0.5), representation (numbers v. graphs; effect coded as numbers = −0.5, graphs = +0.5), graph literacy (centered), and all possible interactions. Numeracy (centered) was included as a covariate. Note that including graph literacy as a predictor variable, yet numeracy only as a covariate, was done in line with a related study,As a robustness check, we nevertheless also ran the same model with numeracy as a predictor (see Furthermore, for a better interpretation of the interaction of 2 predictors, we additionally tested simple effects by analyzing the effect of 1 predictor separately in the subgroups of the other predictor. We use a mixed-effects model because it enables us to both account for within-subjects factors (i.e., time and knowledge type) and to include a continuous predictor (i.e., graph literacy), as suggested by Magezi.Gist and verbatim knowledge scores for numbers versus graphs with separate lines for people with high and low graph literacy, separate panels for T1 (upper panels a and b) and T2 (lower panels c and d), and separate panels for conditions “no choice” (left panels a and c) and “choice” (right panels b and d). Error bars represent 1 standard error of the mean. | PMC10625725 |
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Effects of graph literacy and numeracy | People higher in graph literacy had overall higher knowledge (high: | PMC10625725 |
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Effects of choice | GIST | In contrast to our expectations, choice did not generally improve knowledge (choice: Choice did, however, specifically increase verbatim knowledge (choice: Interestingly, in contrast to (our default) placebo scoring, if we scored gist knowledge with medication-only scoring, choice increased overall knowledge (choice: | PMC10625725 |
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Effects of representation (numerical, graphical) and its interaction with graph literacy | Participants who worked with numbers were overall better than those who worked with graphs (numbers: | PMC10625725 |
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Does Choice Increase Ratings of Accessibility and/or Attractiveness? | REGRESSION | To analyze whether accessibility and attractiveness differed between the “no choice” and “choice” condition, we ran 2 separate linear regression models with accessibility and attractiveness as outcome variables, respectively; the predictors were condition (“no choice” v. “choice”; effect coded), representation (numbers v. graphs; effect coded), and graph literacy (centered) and their interactions. Numeracy (centered) was included as a covariate but did not yield any effect on accessibility and attractiveness (with betas being basically zero) and is thus not further discussed in detail here. For both models, the results were similar when running a model with numeracy as predictor and when excluding numeracy as a covariate or predictor. The results are illustrated in Accessibility (a) and attractiveness (b) scores for numbers versus graphs with separate lines for conditions “no choice” and “choice.” Error bars represent 1 standard error of the mean.Participants’ ratings of accessibility did not differ between graphs and numbers (numbers: Participants generally rated graphs as more attractive than numbers (numbers: | PMC10625725 |
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Discussion | GIST | Not everyone benefits from graphical representations of statistical information, and for some people, numerical representations are actually better suited to foster knowledge.We were first asking which representation gets chosen more often and whether people chose representations in line with underlying skills, particularly graph literacy, but also numeracy. In line with previous research, most participants chose the graphical over the numerical representation (e.g., Nayak et al.Our second question was whether allowing people to choose the representation would yield better objective comprehension and recall of the information, which could be the case if choice fosters the match between people’s abilities and chosen representations. Our results, however, show that choosing does not increase comprehension and recall overall. To test whether this null effect could be attributed to limited power to detect a significant effect, we ran a simulation-based sensitivity analysis following DeBruine and BarrWith regard to different types of knowledge, choice did not affect gist knowledge and recall at all, yet it slightly increased verbatim knowledge compared with the “no choice” condition. However, although this increase in verbatim knowledge was statistically significant, it is unclear whether this increase of about 5 percentage points on 1 knowledge dimension is clinically relevant given a baseline performance of about 70% (across both points in time). Furthermore, whereas having precise verbatim knowledge about clinical options is clearly important, gist knowledge may in fact matter more for making medical decisions.The third and final question was whether subjective ratings of accessibility and/or attractiveness would be increased in the “choice” condition, revealing potential motifs of choosing a particular representation. In line with the general preference for the graphical representation, attractiveness ratings of the graphical representation were higher than those of the numerical representation. Importantly, choice consistently increased ratings of attractiveness in comparison with the randomly allocated representations, for both numbers and graphs. This suggests that perceptions of how attractive particular representations are for individual participants played an important role when they chose between representations. Of course, there could additionally be an effect in the other direction, that is, from choice to attractiveness. It is very well documented that people judge options to be more desirable after they have chosen them, even if desirability was identical before making the choice.Whereas choice did not generally increase rated accessibility, it specifically increased ratings of accessibility for the graphical representation. Yet this increased accessibility did not translate into increased overall knowledge scores, as summarized above. In fact, when looking at bivariate correlations between ratings of accessibility and the various knowledge scores (gist and verbatim knowledge at T1 and T2, respectively), it turns out that they are, by and large, uncorrelated with one another; in one case, there is even one small negative correlation, indicating lower gist knowledge at T1 with higher ratings of accessibility (To summarize, the choice between a graphical and a numerical representation 1) revealed a general preference for the graphical representation, and this preference was not related to abilities (graph literacy and numeracy, respectively); 2) did not yield better comprehension and recall overall; and 3) was correlated with increased attractiveness ratings for chosen representations compared with their randomly allocated counterparts and for graphs additionally with increased perceived accessibility (without translating into increased knowledge). Taken together, letting patients choose the representation is not an efficient way to ensure they receive a representation that they understand or recall well. Although choice improved verbatim knowledge, this limited benefit is not enough to recommend giving patients the opportunity to choose a representation as an approach to improve knowledge of medical information. Rather, these results suggest that people choose the representation they thought of as more attractive and, at least for graphs, the one they believe to more accessible, rather than choosing the one that they objectively comprehend better. | PMC10625725 |
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Limitations | ≈0.72 | Several limitations of the study need to be taken into consideration when interpreting the results. First, the sample consisted of a diverse yet highly educated group of students who are not representative of the general population in Spain. Consequently, they have higher graph literacy scores than an average person randomly drawn from the population (0.81 compared with ≈0.72 in nationally representative samples in Germany and the United StatesThe second limitation is that the information presented to participants was not of personal relevance to them. That is, they could choose a representation independent of how well they understood it without having to fear any real consequences. The results on whether (typically financial) incentives make a difference for behavior are mixed,Furthermore, there are some peculiarities in the data that we would like to discuss transparently. The first peculiarity is that numeracy was not at all related to comprehension, recall, or accessibility ratings (and in some cases even negatively so, even though with a tiny effect size). This is surprising in light of the vast literature showing the impact of numeracy on understanding health-related statistical informationThe second peculiarity is that comprehension and recall were, on average, better with the numerical than with the graphical representation. Whereas a substantial amount of literature suggests that graphical representations are helpful to understand statistical information, | PMC10625725 |
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Conclusion | comprehension and recall of medical information, comprehension and recall | MINOR | People differ in which kind of representation of statistical information they understand best: Some people understand graphical representations better, others are better off with mere numbers. Yet assessing their abilities to understand graphical and numerical information is infeasible in practice. Giving patients the opportunity to decide which representation to receive could have been a very efficient way to provide those information representations to patients that fit their abilities and thus improve comprehension and recall. However, despite some very minor benefits for verbatim knowledge, overall this approach is not sufficient to improve comprehension and recall of medical information. Instead, people seem to choose the representation they perceive as more attractive. Thus, improving knowledge by getting the right representation to the right people would require other methods of tailoring rather than choice, yet those would need to be feasible in practice. As graphical representations were rated as being more attractive and are preferred by a majority, there is another solution to improve knowledge that requires further work, however: to develop better graphical representations that are so clearly designed that they are understandable for broader audiences—including for those with low graph literacy. Important steps in that direction include adding numerical and textual information to graphs that simply describes what can be seen, which has been shown to improve performance and reduce the impact of numeracy, | PMC10625725 |
Supplemental Material | PMC10625725 |
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References | PMC10625725 |
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Introduction | Non-medical use of psychostimulants is common in healthy subjects, often for enhancing cognitive performance in domains such as memory or vigilance ([see Inconsistent results have been found for amphetamine on working memory (WM) [Caffeine is also a psychostimulant that is widely consumed worldwide for its psychomotor and cognitive effects. Although caffeine has less strong pharmacological effects than other strong psychostimulants (such as amphetamines), the qualitative physiological effects of caffeine are expected to be broadly similar as the other stimulants [A main challenge in the assessment of WM performance is that that there is no one generally accepted SWM or VWM model [Caffeine also modulate the dopaminergic system indirectly through adenosine-dopamine receptor heteromer (A2A-D2) [ | PMC10343048 |
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Methods and materials | PMC10343048 |
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Ethical approval | The University of Western Australia (UWA) Human Research Ethics Committee has granted ethical approval for this study (RA/4/1/8056 for experiment 1 and RA/4/20/4558 for experiment 2). The study is registered at the Australian New Zealand Clinical Trials Registry (ACTRN12608000610336, for experiment 1 and ACTRN12618001292268, for experiment 2). | PMC10343048 |
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Participant recruitment | substance-use, schizophrenia-spectrum, first-degree, cardiovascular disorder, word of mouth, ADHD, schizophrenia, psychotic disorders, bipolar affective disorder, neurological illness | CARDIOVASCULAR DISORDER, SEPARATION, SYMPATHOMIMETIC | All forty participants were recruited by word of mouth, lecture announcements, advertisements on campus notice boards, social media, or university-group emails in 2017 and 2018. Participants were informed to abstain from any psychoactive substance (including caffeine) at least 24 hours before the test.Inclusion criteria were being >17 and <60 years of age, and if female, not be pregnant, and be using contraceptives if sexually active and fertile to avoid the potential of harming a fetus. Exclusion criteria included, inability to provide valid consent, sensitivity to d-amphetamine or sympathomimetic amines for the d-amphetamine study or to caffeine in the caffeine study, history of psychotic disorders (schizophrenia, schizophrenia-spectrum, or bipolar affective disorder) in themselves or their first-degree relatives, substance-use dependence, neurological illness, or language difficulties that could interfere with assessment, currently taking any (prescription) medicine that affect cognitive functions, childhood diagnosis of ADHD, women who are pregnant or lactating and cardiovascular disorder risks.The testing sessions were held between 9:00 am to 5:00 pm for a total of two days (with one-week separation) for each participant. As mentioned in the general procedures, the times of the experiments at each session and test were well-controlled to avoid inconsistencies. Transport and lunch were provided with no additional financial incentive. Informed consent and medical assessments by psychiatrists were conducted before the experiment on the first day. The basic demographic information (age, years of education, sex, and weight) was then taken.Both experiments were randomized, double-blind, counter-balanced, placebo controlled cross-over studies with permuted block randomization for drug order. Each participant received both the active drug and placebo in identical gelatin capsules. Half of the participants (n = 10) in each experiment received placebo on the first day and active drug on the second day which followed the first day by at least a week, while the remaining half received active drug first and placebo second (Figs | PMC10343048 |
CONSORT 2010 Flow Diagram 1. | PMC10343048 |
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CONSORT 2010 Flow Diagram 2. | RECRUITMENT | The principal investigator generated the random allocation sequence, allocated participants to each group and only he had access to information that could identify individual participants during or after data collection. The trial staff that were involved in the participant recruitment and data collection did not have the randomization list. | PMC10343048 |
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Experiment 1: D-amphetamine | PMC10343048 |
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Participants | ± | Twenty healthy participants (15 male) with a mean (±SD) age of 22.9 (±5.17) were recruited. They had a mean weight (± SD) of 74.9 (± 14.2) kg and 14.5 (±1.5) years of education. Substance use information was unavailable for one participant: 13 of the participants were regular consumers of caffeinated drinks; 8 of them had used cannabis at least once (6 of them used it in the last two weeks); 11 of them consumed amphetamine at least once in their life (3 of them consumed in the last one year, while 2 of them consumed it in the last three months). None of them were active cigarette smokers (only three of them smoked a month ago). | PMC10343048 |
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Drug and design | D-amphetamine (0.45 mg/kg, PO, Aspen Pharmacare, Australia) was used, giving a mean dosage of 33.7 mg based on the mean weight of the participants of 74.9 kg. Similar sizes and numbers of capsules containing either placebo (glucose) or 0.45 mg/kg d-amphetamine were prepared using 1, 2.5, 5, and 10 mg d-amphetamine sulfate tablets. This dose of d-amphetamine was selected based on previous experiments in healthy subjects demonstrating significant effects on a range of illusory and psychophysiological measures [ | PMC10343048 |
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Experiment 2: Caffeine | PMC10343048 |
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Participants | Twenty healthy participants (14 males) with the mean (±SD) age of 22.2 (± 4.1) were recruited. They had a mean weight (± SD) of 80.3 kg (± 20.0) and 14.6 (±1.5) years of education. All except three were a regular consumer of caffeine (have taken at least one cup of caffeine-containing drinks per day, with 1.6 (±1.1) mean (±SD) cup of coffee or tea). Three of them consumed cannabis in the last two months, four of them smoke cigarette and two of them consumed amphetamine in the last month. | PMC10343048 |
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Drug and design | For this experiment, 200 mg of caffeine was administered in the morning (PO, BID; caffeine 200mg, PROLAB nutrition LLC, Chatsworth, USA). Caffeine was administered in gelatin capsules (size 0). Powdered glucose (Placebo) was also separately placed in the same type of capsule. This dose of caffeine was selected based on previous studies on cognitive tasks [ | PMC10343048 |
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General procedures for both experiments | PMC10343048 |
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Psychological scale | Five rating scales were conducted once each day to measure Psychosis-like experiences (PLE): Brief Psychiatric Rating Scale (BPRS) [ | PMC10343048 |
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Physiological measures | BLOOD | Physiological changes were measured to assess whether the drug was active or not during the WM tests. Blood pressure (BP), temporal vein temperature (Temp) and heart rate (HR) were measured in triplicate five times each day to follow the time course of the drug and placebo effects on Systolic BP (SBP), Diastolic BP (DBP), HR, and Temp. BP (mmHg) and HR [in beat per minute (bpm)] were measured. The consecutive five physiological testing times were 0, 60, 110, 210, and 370 min post-d-amphetamine administration, while 0, 60, 210, 300, and 390 min post-caffeine administration. | PMC10343048 |
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Working memory | WM tests were conducted in a well-lit room. We used forward spatial span (for SWM) and digit span (for VWM), from the Wechsler Adult Intelligence III (WAIS-III) [The same scoring criteria (the total scored and the maximum obtained) were used for both digit span and spatial span tasks. The maximum obtained indicates the maximum number of trials the participant scored without any error, while the total scored is the total number of trials correctly scored from the 16 trials until the participant fails the same item on subsequent trials. A measure of WM consisted of the average of the digit and spatial span scores across the delay conditions. Similar overall scores were calculated for SWM and VMW. | PMC10343048 |
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Spatial Span | Spatial span is a visuospatial analogue of the digit span test. This test was conducted at 90 min of post-d-amphetamine administration (0.45 mg/kg) and at 60 min post-caffeine administration. For each trial, ten randomly arranged blue squares (Psychcorp Mark) were shown on the table. The task began with the simplest level of a two-box sequence. After each successful trial, the number of boxes in the sequence was increased by one to a maximum of nine. There were eight items, each with two trials of the same box number (i.e., a total of 16 trials). There were four delay conditions (0, 4, 6, and 8 s delay): the participant was asked to touch the boxes in the same order (forward) right after the examiner (0 s delay), and repeated for 4, 6, and 8 s delays (but different compositions). In addition to the intrinsic differences among tasks, delay condition between encoding and maintenance phase might be a key factor in WM performance [ | PMC10343048 |
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Digit Span | This test was carried out after the spatial test, at 210 min of post-d-amphetamine administration and at 120 minutes of post-caffeine administration. The digits were pronounced in 1 s intervals by the examiner. The participant was asked to repeat the digits in the same order (forward) right after the examiner (0 s delay), and repeated for 4, 6, and 8 s delays (but different digit compositions). The task of recalling the digits began with the simplest level of a two-digit sequence. After each successful trial, the number of digits in the sequence was increased by one to a maximum of nine. There were eight items (the minimum item was with two digits, while the maximum was nine digits), two trials of the same length of digits for each item (i.e., a total of 16 trials). | PMC10343048 |
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Statistical analysis | generalised | The statistical analysis was performed using R programming version 3.5.3 (R Core Development Team 2018) and dply, ez, lme4, plyr, Rmisc, stats, sm packages. Normal Q-Q plots were used to check the residuals of the data. A repeated measure analysis (ANOVA) was used to analyse the data if the residuals indicated a sufficiently normal distribution. Then paired t-tests with exact Bonferroni corrections were used for pairwise comparisons between the drug and placebo condition. Wilcoxon signed rank test with continuity correction (and with Bonferroni corrections) was used if the residuals were not distributed normally. Subsequently, physiological measurements and WM were analysed using ANOVA with Greenhouse–Geisser epsilon if the assumption of sphericity was violated, and generalised η | PMC10343048 |
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Power analysis | We used G*Power 3.1 power calculator, and based our predicted mean difference (Drug-Placebo) and standard deviation of the difference on findings in our lab on the effect of DEX on the "embodiment" component of the RHI (paired samples t-test) indicating an effect size of 0.43 with alpha = 0.05, with a power of 0.80 (80%), with a two-tailed test. | PMC10343048 |
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Results | PMC10343048 |
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Experiment 1: D-amphetamine | PMC10343048 |
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D-amphetamine effects on physiology | There were significant effects of d-amphetamine on heart rate (F[1, 19] = 49.8, p < 0.001, ƞ | PMC10343048 |
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D-amphetamine effects on VWM and SWM | ANOVA with delay and drug as within-subject factors and drug order as a between-subjects factor indicated that there were no drug by delay interactions on VWM (maximum obtained F[3, 57] = 0.5, p = 0.67, ƞAs shown in | PMC10343048 |
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The effect of d-amphetamine (0.45 mg/kg, PO) and placebo on working memory (WM) for maximum obtained and total scored. | Data are presented as maximum scored (A and C) or total scored (B and D) vs. delay conditions. A) The effect of d-amphetamine on spatial WM (maximum scored), relative to placebo; B) The effect of d-amphetamine on spatial WM (total scored), relative to placebo; C) The effect of d-amphetamine on verbal WM (maximum scored), relative to placebo; D) The effect of d-amphetamine on verbal WM (total scored), relative to placebo. There were no significant effects of d-amphetamine on WM, VWM or SWM.There were significant effects of delay on VWM for the total scored (F[2.3, 43.9] = 22.3, p = 0.004, ƞ | PMC10343048 |
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D-amphetamine effect on PLE | As shown in | PMC10343048 |
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Box plot of the effect of d-amphetamine (0.45 mg/kg, PO) and caffeine on Psychosis-like experiences (PLE). | D-amphetamine but not caffeine significantly increased PLE scores, relative to placebo (p < 0.001). C: Caffeine, D: D-amphetamine, P: Placebo. | PMC10343048 |
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Effects of d-amphetamine and caffeine on each Psychological scale. | ** significant at p < 0.01* significant at p < 0.05. Data are presented as Mean±SD. | PMC10343048 |
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PLE and working memory | Pearson’s correlation was used to assess how changes in PLE scores (d-amphetamine–placebo) relate to WM change scores (d-amphetamine–placebo). There was a significant negative correlation between d-amphetamine induced changes in PLE and changes in WM (maximum obtained) at the 8 s delay (r = -0.47, p = 0.03, n = 20), but not at 0 s (r = 0.28, p = 0.22, n = 20), 4 s (r = 0.09, p = 0.69, n = 20), or 6 s (r = 0.10, p = 0.67, n = 20).To assess which span tasks influenced the association between the WM change and PLE change, we did separate analysis for each SWM and VWM at each delay condition. There was a significant negative correlation between changes in PLE and changes in SWM (r = -0.58, p = 0.006, n = 20), but not between changes in PLE and changes in VWM (r = -0.01, p = 0.96, n = 20) at the 8 s delay, indicating the correlation between WM and PLE was mainly influenced by SWM. | PMC10343048 |
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Experiment 2: Caffeine | PMC10343048 |
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Caffeine effect on physiology | Analysis of variance with time and drug as within-subject factors and drug order as a between-subjects factor showed significant main effects of caffeine on systolic blood pressure (F[1, 19] = 27.9, p = 0.00004, ƞ | PMC10343048 |
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Caffeine effect on PLE | Launay-Slade | Wilcoxon signed rank tests with continuity correction revealed that there were no significant effects of caffeine on any of the PLE scales: BPRS (V = 87, p = 0.63), MIS (V = 70.5, p = 0.91), and PAS (V = 96, p = 0.35), Launay-Slade (V = 5.5, p = 0.17) and SAPS (V = 91, p = 0.82). | PMC10343048 |
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Caffeine effect on VWM and SWM | ANOVA with delay and drug as within-subjects factors and drug order as a between-subjects factor did not indicate significant drug by delay interactions for SWM (maximum obtained F[3, 57] = 0.48, p = 0.69, ƞThe effect of caffeine (200 mg, BID, PO) on SWM (a and b) and VWM (c and d) during forward tasks. Maximum obtained for SWM (a), total scored for SWM (b), maximum obtained for VWM (c), and total scored for VWM (d). There were no significant effects of caffeine on maximum obtained (a and c) and total scored (b and d) at each delay condition. (N = 20, for all).Although there were no main or interactional effects of caffeine on WM, SWM or VWM, there were significant effects of delay on SWM for the maximum obtained (F[3, 57] = 6.2, p = 0.0009, ƞ | PMC10343048 |
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PLE and working memory | Although caffeine did not significantly influence PLE or WM, to compare the effects of caffeine and dexamphetamine we conducted the same correlation analysis. Changes in PLE scores (caffeine–placebo) were correlated with WM (maximum obtained) change scores (caffeine–placebo). There were no significant correlations between caffeine induced changes in PLE and changes in WM (r = -0.19, p = 0.40, n = 20), SWM (r = -0.11, p = 0.65, n = 20), VWM (r = -0.20, p = 0.38, n = 20). There was also no significant correlation between caffeine induced changes in PLE and changes in WM at each delay: the 0 s (r = -0.18, p = 0.44, n = 20), but not at 4 s (r = -0.25, p = 0.27, n = 20), 6 s (r = -0.23, p = 0.32, n = 20), and 8 s (r = 0.05, p = 0.84, n = 20). | PMC10343048 |
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Discussion | The aim of the present two randomized studies was to investigate the effect of d-amphetamine (0.45 mg/kg, PO) and caffeine (200 mg, PO) on SWM and VWM performance in healthy subjects following delays in recall. The results showed that there are no main effects of d-amphetamine on the SST or the DST, relative to placebo. Likewise, caffeine did not affect performance on the SST or the DST, relative to placebo, which is consistent with previous reports on WM tests [Although there are some studies that did not find effects of amphetamine on SWM, other studies did detect effects of amphetamine SWM ([ | PMC10343048 |
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The effect of D-amphetamine and caffeine on WM | As there are no one generally accepted model to measure WM [In the present study, we used DST and SST to measure VWM and SWM, respectively. The DST is a simple span tasks used to measure auditory WM. SST is comparatively more complex tasks [We failed to find a main effect of d-amphetamine on SWM, which is in agreement or comparable with previous studies on the SWM effect of d-amphetamine in various SWM task performances [Although we used higher doses than previous studies that assessed the effect of d-amphetamine on SWM, we failed to find main effects of d-amphetamine on SST performance. In addition, we applied four delay conditions in order to examine the maintenance component of WM, but the results showed that d-amphetamine did not influence WM in the presence of delays. A previous study [The present result also showed that d-amphetamine does not affect VWM on the DST under four delay conditions, which is in agreement with previous studies that used backward DST, forward DST or both to assess VWM [With respect to caffeine, the present finding is consistent with previous reports on the acute effects of caffeine on SWM (n-back test) [ | PMC10343048 |
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PLEs in response to d-amphetamine and caffeine | The present study showed that d-amphetamine (0.45 mg/kg, PO), but not caffeine (200 mg), increased PLE scores. Previous reports showed that the level of dopamine released after dexamphetamine administration correlates with PLE scores [In the present study, caffeine did not significantly affect PLE measures. However, we predicted that caffeine might slightly increase schizotypy scores as dopamine mediates some of the behavioural effects of adenosine antagonists [There are several double-blind placebo-controlled studies in healthy participants that showed caffeine consumption increases subjective effects (such as arousal) [The present results also showed that caffeine increased physiological (blood pressure) measurements without having effects on WM, indicating that the drug was active during cognitive tasks. Previous studies reported that low to moderate doses of caffeine increase systolic and diastolic blood pressure ([ | PMC10343048 |
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Strength and limitations of the study | The main strength of the present study was its study design (placebo controlled, within subject studies). It investigated the potential effects of d-amphetamine and caffeine on SWM and VWM performance using SST and DST at different delay conditions. This study used d-amphetamine at a moderate-high dose (~33 mg), about two to three times higher than that used in most previous challenge studies. There are, however, limitations to be considered for future studies. First, the major limitation is the sample size; confidence would be increased with a larger sample size. Importantly, the sample size of female participants should be increased to identify sex-dependent effects as ovarian hormone may influence drug response [ | PMC10343048 |
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Conclusions | A moderate dose of d-amphetamine increased PLE on different scales. However, d-amphetamine does not directly affect performances on SST, but may impair SWM through its effects on PLEs that manifest during longer WM delays. In addition, moderate doses of caffeine do not affect performance on SST and DST. Overall, the present findings indicate that moderate dose of d-amphetamine and moderate doses of caffeine do not directly affect performances on DST or SST with and without delays. | PMC10343048 |
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Supporting information | PMC10343048 |
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Consort 2010 checklist for dexamphetamine and caffeine studies. | (DOC)Click here for additional data file. | PMC10343048 |
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Dexamphetamine study participant information form. | (PDF)Click here for additional data file. | PMC10343048 |
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Caffeine study participant information form. | (PDF)Click here for additional data file. | PMC10343048 |
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Caffeine approval letter. | (PDF)Click here for additional data file. | PMC10343048 |
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Dexamphetamine and caffeine studies test description. | (PDF)Click here for additional data file. | PMC10343048 |
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Dexamphetamine study protocol. | (PDF)Click here for additional data file. | PMC10343048 |
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Dexamphetamine working memory data. | (PDF)Click here for additional data file. | PMC10343048 |
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Caffeine working memory data. | (CSV)Click here for additional data file. | PMC10343048 |
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Caffeine study protocol. | (CSV)Click here for additional data file.The University of Western Australia (UWA-HDR) provided a PhD scholarship for FMK. We would like to thank each volunteer who participated in this study, and all colleagues who assisted in the data collection phase. | PMC10343048 |
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Abbreviations | BLOOD | Diastolic Blood Pressuredorsolateral prefrontal cortexprefrontal cortexSpatial Working MemorySystolic Blood PressureVerbal Working MemoryWorking Memory | PMC10343048 |
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References | PMC10343048 |
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Abstract | PMC10013940 |
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Background | ESSENTIAL TREMOR | Propranolol, a nonselective beta‐adrenergic blocker, has long been used as one of the standard treatments for essential tremor (ET). Repetitive transcranial magnetic stimulation (rTMS) has also been used for a long time as a substitution therapy for ET patients. | PMC10013940 |
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Objective | The main aim of this study was to evaluate the antitremor effect of 1‐Hz (low‐frequency) cerebellar rTMS and compare it to the use of propranolol in ET patients. | PMC10013940 |
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Methods | In this single‐blinded, randomized, controlled pilot study, a total of 38 patients with ET were randomized into two groups. One group ( | PMC10013940 |
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Results | tremor, disability | Low‐frequency rTMS of the cerebellum significantly improved tremor severity, specific motor tasks (writing, spiral drawing, and pouring), and FTM total scores on days 10 and 30. Nevertheless, we found no significant difference in functional disability at any point in time ( | PMC10013940 |
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Conclusion | cerebellar low‐frequency | We conclude that both cerebellar low‐frequency rTMS and propranolol could be effective treatment options for patients with ET, but it is not clear which method is more effective.This paper is the first study to compare the effects of rTMS and medication for ET patients. This will help healthcare providers and ET patients select the best treatment.
Yue Lv and Mengran Wang are co‐authors and contributed equally to this article. | PMC10013940 |
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INTRODUCTION | tremor, head tremor, movement disorders | ESSENTIAL TREMOR, MOVEMENT DISORDERS | Essential tremor (ET) is one of the most frequent movement disorders and is defined as 4–12 Hz kinetic or postural tremor mainly involving the bilateral upper region with or without head tremor or tremor in other locations (Bhatia et al., Existing studies indicate that propranolol and primidone remain the preferred oral agents for ET, and propranolol can significantly reduce the amplitude of tremor (Schneider & Deuschl, As the amplitude of the tremor increased, medication treatment became less effective. Surgical approaches often have been used for drug‐refractory ET, mainly consisting of deep brain stimulation and thalamotomy procedures with radiofrequency, gamma knife radiosurgical thalamotomy, and, most recently, focused ultrasound thalamotomy (Dallapiazza et al., However, existing studies did not compare the efficacy of propranolol and rTMS for ET patients. We present a prospective study to further evaluate the efficacy of propranolol (oral medication) compared with cerebellar low‐frequency rTMS in patients with ET. This will help healthcare providers and ET patients select the best treatment. | PMC10013940 |
METHODS | PMC10013940 |
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Participants | MOVEMENT DISORDER | Thirty‐eight patients with ET participated in the study. They were all recruited from the Department of Neurology in the General Hospital of Ningxia Medical University (Yinchuan, Ningxia, China). These patients were diagnosed based on Movement Disorder Society (MDS) criteria (Bhatia et al., All participants signed written consent in advance of the intervention. All protocols for this study were approved by the Institutional Review Board of the General Hospital of Ningxia Medical University. | PMC10013940 |
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Procedures | tremor | Subjects were randomized into two groups; one group (The Fahn–Tolosa–Marin (FTM) clinical scale, which consists of three subscales, was used to evaluate clinical effects. Part A evaluates tremor location/severity (amplitude), Part B assesses specific motor tasks (writing, spiral drawing, and pouring using dominant and nondominant hands), and Part C measures functional disability due to tremor (speaking, eating, drinking, hygiene, dressing, writing, working, and social activities of daily living) (Fahn et al., | PMC10013940 |
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rTMS cerebellar stimulation | CONTRACTIONS | In the rTMS group, patients received 600 pulses of rTMS in each cerebellar hemisphere at a frequency of 1 Hz and an intensity of 90% of the resting motor threshold (RMT) for 10 consecutive days. There were 20 trains for each 1‐Hz rTMS, and each train was performed for 30 s and followed by a 5‐s break, and each treatment lasted approximately 20 min for every day. The RMT was measured based on the lowest stimulation intensity required to produce only five visible contractions out of 10 stimulations of a target muscle (the right abductor pollicis brevis muscle in our case). We employed rTMS with a figure‐eight coil connected to a Magstim Rapid | PMC10013940 |
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Statistical analysis | ±, SD | All statistics were performed using IMB SPSS for Windows, Version 21.0 (Armonk, NY), and all graphs were generated using GraphPad Prism 8.0. Continuous variables were expressed as the mean ± SD or median (25th percentile, 75th percentile), whereas categorical variables were expressed as percentages (%). Continuous variables used student's | PMC10013940 |
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RESULTS | bradycardia, syncope, seizure, dizziness, headache, hypotension | ADVERSE EFFECTS | All 38 patients received their intended treatments. Twenty patients received rTMS of the bilateral cerebellum for 10 days, and all subjects tolerated rTMS sessions well without severe adverse effects (i.e., dizziness, headache, seizure, syncope). Eighteen patients received medical treatment with oral propranolol for 30 days. The initial dose was 30 mg/day, and the dose was increased to 60 mg/day after 5 days, then to 90 mg/day after 10 days, and continued thereafter for 20 days. None of the participants reported any adverse side effects (i.e., bradycardia, hypotension). | PMC10013940 |
General clinical data | tremor | Of the 38 patients, 19 (50.0%) were female. Twenty‐two subjects (57.9%) had a positive family (first‐ or second‐degree relatives) history of ET. The mean age of the patients was 55.50 ± 13.55 years, and the mean duration of the tremor was 10.08 ± 8.30 years. All patients presented with hand tremor. Other locations of tremor were head (Baseline characteristics of the participantsAbbreviations: FTM, Fahn–Tolosa–Marin clinical scale; rTMS, repetitive transcranial magnetic stimulation. | PMC10013940 |
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rTMS group | ±, tremor | For the rTMS group, there was no significant effect in any clinical aspects of tremor: FTM score Part A, tremor severity (Fahn–Tolosa–Marin (FTM) clinical scale of ET patients before and after cerebellar rTMS (mean ± SD)Abbreviation: rTMS, repetitive transcranial magnetic stimulation. | PMC10013940 |
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Propranolol group | ±, tremor, SD | No aspect of tremor improved significantly at day 5 and day 10 after application of propranolol, and there were no obvious differences for FTM subscales and total score, including tremor severity (day 5 [Fahn–Tolosa–Marin (FTM) clinical scale of ET patients before and after oral propranolol (mean ± SD) | PMC10013940 |
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Comparisons between two groups | tremor | Comparisons between the two groups indicated that for the FTM total score, the treatment difference (rTMS effect‐propranolol effect) was not significant on day 5 (Comparison of Fahn–Tolosa–Marin clinical scale between repetitive transcranial magnetic stimulation group and propranolol group on baseline, day 5, day 10, and day 30. (a) FTM total score. (b) FTM score Part A, tremor severity. (c) FTM score Part B, specific motor tasks. (d) FTM score Part C, functional disability. | PMC10013940 |
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DISCUSSION | tremor, functional disability, dysfunction of the cerebellum | PATHOGENESIS, MOVEMENT DISORDERS | ET is one of the most common movement disorders, and multiple treatments are available (Sharma & Pandey, In our study, we found that when patients took propranolol orally at a dose of 30 or 60 mg for the first 10 days, there was no significant change in any of the FTM subscores or the total score. We observed that there was a significant reduction in tremor severity and significant improvement in functional disability (including writing/drawing/pouring of water) in patients when the dose was increased to 90 mg and administered for another 20 days. According to the evidence‐based ET treatment guidelines from the American Academy of Neurology, class I evidence supports the successful use of propranolol in ET treatment (Zesiewicz et al., Our research results also presented that there was no statistically significant difference in the therapeutic effect between rTMS and propranolol at any time point. In a recent single‐center, single‐blinded, randomized, sham‐controlled pilot study, all patients kept taking propranolol at their original dosage during all rTMS applications of the same protocol as our study, and they concluded that rTMS as an “add‐on” treatment had no obvious effect on ET patients who took propranolol (Shin et al., Previous studies have shown that dysfunction of the cerebellum is crucial in the pathogenesis of ET. Using a combination of electromyography and fMRI, researchers have found increased tremor‐related activity in multiple regions of the bilateral cerebellum of ET patients (Maas et al., When interpreting our results, some limitations of our study should be taken into account. First, since we did not design a sham stimulation control during rTMS treatment, we cannot completely rule out the placebo effect on ET patients. In a double‐blind, sham‐controlled, crossover, add‐on clinical trial, patients were divided into two groups to receive rTMS and sham stimulation treatments and crossed over after a 2‐month washout period. In this study, one patient who received sham stimulation had at least a 70% reduction in the severity of tremor on day 5 compared with the baseline total FTM scores. They also found that compared with sham stimulation on day 5, 12, or 30, the total FTM scores in rTMS did not significantly improve (Olfati et al., | PMC10013940 |
CONCLUSION | tremor | Our findings suggest that 1‐Hz cerebellar rTMS is a relatively safe and potentially effective noninvasive treatment technique for ET patients that can reduce the amplitude of tremor and improve the patient's specific motor tasks. Meanwhile, because of its advantages of convenience, effectiveness, and relatively cheap price, rTMS is easy to be accepted by patients. And the same effect could also be observed in treatment with propranolol. However, we did not find any differences between the two treatments. Future studies should include larger sample sizes of ET patients to explore other stimulation sites and parameter selection for rTMS and exploit more rigorous designs, such as sham stimulation, to address the placebo effect and other limitations. | PMC10013940 |
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AUTHOR CONTRIBUTIONS | Mengran | The work described here was done in mutual assistance with all the authors. Haining Li contributed to the research design and reviewed and edited the manuscript. Jiang Cheng collected references and revised the manuscript. Yue Lv completed the data collection, performed statistical analysis, and drafted the manuscript. Juan Yang and Mengran Wang conducted data collection. All the authors read and approved the final version of the manuscript. | PMC10013940 |
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CONFLICT OF INTEREST STATEMENT | The authors declare no conflicts of interest. | PMC10013940 |
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PEER REVIEW | The peer review history for this article is available at | PMC10013940 |
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DATA AVAILABILITY STATEMENT | The datasets used and analyzed in the current study are available from the corresponding author on reasonable request. | PMC10013940 |
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REFERENCES | PMC10013940 |
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Background | neuromuscular block, residual neuromuscular blockade | Neostigmine used to reverse the muscle relaxants should be guided by neuromuscular monitoring, as the degree of spontaneous pre-reversal recovery is the key to success to reverse the neuromuscular block. But neuromuscular monitoring is not always available for some patients during anesthesia and, in consequence, we need to use other clinical judgment to guide the use of neostigmine to reverse the neuromuscular block. In this trial, we aimed to evaluate the incidence of residual neuromuscular blockade (rNMB) in pediatric patients with routine use of neostigmine after recovery of spontaneous breathing compared with the patients with the use of neostigmine guided by neuromuscular monitoring. | PMC9824919 |
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Methods | hypoxia, hernia, muscle paralysis | ADVERSE EVENTS, HYPOXIA | A parallel, randomized, controlled noninferiority study was conducted. We enrolled aged 3 months to 12 years old patients who underwent inguinal hernia repair under general anesthesia. The enrolled patients were randomly divided into experimental and control groups. After surgery, children in the experimental group were given 0.02 mg/kg neostigmine after recovery of spontaneous breathing. Children in the control group were given 0.02 mg/kg neostigmine when the train-of-four (TOF) ratio was between 0.4 and 0.9. However, no neostigmine was administered if the TOF ratio was higher than 0.9. The primary outcome was the incidence of rNMB after extubation (TOF ratio < 0.9). Secondary outcomes included the incidence of neostigmine-induced muscle paralysis, end of surgery – extubation interval, end of surgery – exit OR interval, the length of stay in the PACU, the incidence of hypoxia in the PACU, the number of children who required assisted ventilation during the PACU stay, and neostigmine-related adverse events. | PMC9824919 |
Results | A total of 120 children were included in this study, with 60 in the experimental group and 60 in the control group. There was no significant difference in the incidence of rNMB after extubation between the groups (45/60 vs 44/60, RR 1.02 [95% CI, 0.83 to 1.26], | PMC9824919 |
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