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Background: Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known. Methods: EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (IDH) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0–2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union’s Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028. Discussion: EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma. Trial registration: ClinicalTrials.gov NCT05904119.

Background Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known. Methods EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m$^{2}$ every 6 weeks) or lomustine (110 mg/m$^{2}$ every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (IDH) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0–2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union’s Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028. Discussion EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma. Trial registration ClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023

While the impact of the gut microbiota on brain and behavior is increasingly recognized, human studies examining this question are still scarce. The primary objective of the current study was to explore the potential relationships between the gut microbiota composition, motor cortical excitability at rest and during inhibitory control, as well as behavioral inhibition, in healthy volunteers and in patients suffering from alcohol use disorder. Motor cortical excitability was examined using a range of transcranial magnetic stimulation (TMS) measures probed at rest, including the recruitment curve, short and long intracortical inhibition, and intracortical facilitation within the primary motor cortex. Moreover, TMS was applied during a choice reaction time task to assess changes in motor excitability associated with inhibitory control. Finally, behavioral inhibition was investigated using a neuropsychological task (anti-saccade). Overall, our results highlight several interesting correlations between microbial composition and brain measures. Hence, higher bacterial diversity, as well as higher relative abundances of UGC-002 and Christensenellaceae R-7 group were correlated with stronger changes in motor excitability associated with inhibitory control. Also, higher abundance of Anaerostipes was associated with higher level of corticospinal excitability. Finally, relative abundances of Bifidobacterium and Faecalibacterium were positively related to performance in the neuropsychological task, suggesting that they might have a positive impact on behavioral inhibition. Although correlation is not causation, the present study suggests that excitatory and inhibitory brain processes might be related to gut microbiota composition.

In Parkinson’s disease, neurophysiological abnormalities within the primary motor cortex have been shown to contribute to cardinal symptoms such as bradykinesia, but the exact modalities are still uncertain. Here, we propose that such impairment could involve alterations of mechanisms shaping motor activity specifically during voluntary movement preparation. Indeed, several past studies in healthy populations have suggested that a strong suppression of corticospinal excitability called “preparatory suppression” – propels movement execution by increasing motor neural gain. Thus, we hypothesized that a gradual alteration to this mechanism may contribute to progressive motor slowness in Parkinson’s disease. We also predicted a benefit of dopamine medication in restoring correct motor neural activity during action preparation. To test these hypotheses, we investigated preparatory suppression on two consecutive days in 29 Parkinson’s disease patients (ON and OFF medication) and 29 matched healthy controls. Single-pulse transcranial magnetic stimulation was applied over both primary motor cortices, eliciting concurrent motor-evoked potentials in the two hands, while subjects were either at rest or prepared a left- or right-hand response in an instructed-delay choice reaction time task. Preparatory suppression was assessed by expressing the amplitude of motor potentials evoked during movement preparation relative to those obtained at rest. These neurophysiological measures were cross-analysed with task behaviour and clinical data. Contrary to healthy controls, Parkinson’s disease patients showed a lack of preparatory suppression, which appeared to depend on disease progression, but not on dopamine medication. Indeed, in relatively early disease stages, patients still exhibited partial preparatory suppression, while in later stages, they lacked it completely and even exhibited a tendency for corticospinal facilitation in the hand selected for movement execution. As expected

BACKGROUND: In Parkinson's disease (PD), neurophysiological abnormalities within the primary motor cortex (M1) have been shown to contribute to bradykinesia, but exact modalities are still uncertain. We propose that such motor slowness could involve alterations in mechanisms underlying movement preparation, especially the suppression of corticospinal excitability-called "preparatory suppression"-which is considered to propel movement execution by increasing motor neural gain in healthy individuals. METHODS: On two consecutive days, 29 PD patients (on and off medication) and 29 matched healthy controls (HCs) underwent transcranial magnetic stimulation over M1, eliciting motor-evoked potentials (MEPs) in targeted hand muscles, while they were either at rest or preparing a left- or right-hand response in an instructed-delay choice reaction time task. Preparatory suppression was assessed by expressing MEP amplitudes during movement preparation relative to rest. RESULTS: Contrary to HCs, PD patients showed a lack of preparatory suppression when the side of the responding hand was analyzed, especially when the latter was the most affected one. This deficit, which did not depend on dopamine medication, increased with disease duration and also tended to correlate with motor impairment, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (both total and bradykinesia scores). CONCLUSIONS: Our novel findings indicate that preparatory suppression fades in PD, in parallel with worsening motor symptoms, including bradykinesia. Such results suggest that an alteration in this marker of intact movement preparation could indeed cause motor slowness and support its use in future studies on the relation between M1 alterations and motor impairment in PD. © 2022 International Parkinson and Movement Disorder Society.

By applying transcranial magnetic stimulation (TMS) over primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) in muscles of the contralateral hand during reaction time (RT) tasks, many studies have reported a strong global suppression of motor excitability during action preparation, a phenomenon called preparatory inhibition. Several hypotheses have been put forward regarding the role of this broad suppression, with the predominant view that it reflects inhibitory processes assisting action selection. However, this assumption is still a matter of debate. Here, we aimed at directly addressing this idea by comparing MEPs in a task that required subjects to select a finger response within a set of predefined options (choice RT task: left or right index finger abduction) or when subjects simply had to provide the same finger response on every trial, in the absence of choice (simple RT task). Moreover, we minimized any effect that could be associated with other forms of inhibition. In both versions of the task, TMS was applied on both M1 (double-coil protocol) at several time points between the go signal and the left or right index finger response, eliciting MEPs bilaterally in the prime mover (index finger agonist) and in an irrelevant muscle (pinky agonist). Overall, MEP suppression was moderate in this study compared to past research; it was only found for the irrelevant muscle. As such, MEPs in the index agonist were facilitated when elicited in a responding hand (e.g. left MEPs preceding left responses) and remained mostly unchanged in a non-responding hand (e.g. left MEPs preceding right responses). In contrast, MEPs were almost always suppressed in the pinky muscle when elicited in the non-responding hand. This finding contrasts with previous studies where preparatory inhibition usually concerns both relevant and irrelevant muscles. Yet importantly, the suppression was more consistent in the choice than in the simple RT task, supporting the view that

Adaptive sensorimotor interaction requires fine movement preparation (Gallivan, Chapman, Wolpert, & Flanagan, 2018). By applying transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) to elicit motor evoked potentials (MEPs) in muscles of the contralateral hand (Bestmann & Duque, 2016), many studies have shown that action preparation is associated with a transient decrease in the excitability of the corticospinal pathway; this phenomenon has been referred to as preparatory inhibition (Duque, Greenhouse, Labruna, & Ivry, 2017). Intriguingly, while a growing number of studies support the extreme robustness of this effect, the role of such preparatory inhibition remains fundamentally unclear. Our long-term goal is to test the hypothesis that preparatory inhibition reflects the operation of processes that assist action preparation at the level of both choice and motor control. In the context of choice, preparatory inhibition would serve to regulate a speed-accuracy tradeoff (SAT), with more inhibition favoring accuracy over speed. Furthermore, in the context of motor control, preparatory inhibition would facilitate the fine-tuning of muscle activity, with stronger inhibition increasing the gain of motor commands. To test these hypotheses, we recently developed a new experimental task that combines the Tokens Task (Thura & Cisek, 2014, 2017) and some features of the Pac-Man video-game (https://fr.wikipedia.org/wiki/Pac-Man). In brief, at each trial of this task, called the “Tok-Man” Task, tokens jump one-by-one from a central circle to one of two lateral circles. Subjects must then foresee which of both circles will receive more tokens by the end of the trial, and report it by pressing a button on a keyboard with their left or right index finger. Subjects may respond whenever they feel confident to make a choice, but necessarily before the last token jump. Once their choice is made, the motor control part of the trial initiates, by showing a Pac-Man o

Impaired inhibitory control contributes to the development, maintenance, and relapse of alcohol-dependence, but the neural correlates of this deficit are still unclear. Because inhibitory control has been labeled as an executive function, most studies have focused on prefrontal areas, overlooking the contribution of more "primary" structures, such as the motor system. Yet, appropriate neural inhibition of the motor output pathway has emerged as a central aspect of healthy behavior. Here, we tested the hypothesis that this motor inhibition is altered in alcohol-dependence. Neural inhibitory measures of motor activity were obtained in 20 detoxified alcohol-dependent (AD) patients and 20 matched healthy subjects, using a standard transcranial magnetic stimulation procedure whereby motor-evoked potentials (MEPs) are elicited in a choice reaction time task. Moreover, behavioral inhibition and trait impulsivity were evaluated in all participants. Finally, the relapse status of patients was assessed 1 year after the experiment. As expected, AD patients displayed poorer behavioral inhibition and higher trait impulsivity than controls. More importantly, the MEP data revealed a considerable shortage of neural motor inhibition in AD patients. Interestingly, this neural defect was strongest in the patients who ended up relapsing during the year following the experiment. Our data suggest a strong motor component in the neural correlates of altered inhibitory control in AD patients. They also highlight an intriguing relationship with relapse and the perspective of a new biomarker to follow strategies aiming at reducing relapse in AD patients.

OBJECTIVES: Motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) show a profound suppression when elicited during the instructed-delay of reaction time (RT) tasks. One predominant hypothesis is that this phenomenon, called "preparatory inhibition", reflects the operation of processes that suppress motor activity to withhold prepared (but delayed) responses, a form of impulse control. In addition, a startling acoustic stimulus (SAS) - a loud and narrow sound - can trigger the release of prepared responses in RT tasks. We predicted that, if such premature release is clearly forbidden, then anticipating a SAS during delay periods may be associated with increased preparatory inhibition for greater impulse control. METHODS: Subjects performed a behavioural (n=16) and TMS (n=11) experiment. Both used a choice RT task that required subjects to choose a response based on a preparatory cue but to only release it after an imperative signal. SAS and TMS pulses were elicited at the end of the delay period and subjects were asked to do their best to only release their response after the imperative signal, even in the presence of SAS. SAS could be either rare or frequent, in separate blocks. RESULTS: Consistent with the literature, SAS shortened RTs, especially when they occurred frequently. Moreover, MEPs were suppressed when subjects delayed prepared responses but this preparatory inhibition did not depend on whether SAS were frequent or rare. DISCUSSION: The stronger RT shortening with frequent rather than rare SAS may be due to increased attention and/or reduced reactive inhibition to SAS, leaving preparatory inhibition unaffected.

Recent transcranial magnetic stimulation studies have shown that the motor output pathway shows a profound inhibition during the preparation of an action. This phenomenon, called “preparatory inhibition”, remains incompletely understood, as it is still unclear which neural structures support it and what function it exactly serves during action preparation. In the current study, we tested this preparatory inhibition in Parkinson’s disease (PD) patients and matched healthy control subjects. The aim was to better understand the role of basal ganglia (which are dysfunctional in PD) and the influence of dopamine replacement therapy on motor inhibition during action preparation.