•Neural source of motor preparatory suppression remains largely unknown.•Extent of preparatory suppression was related to structural brain measures.•Thinner medial prefrontal cortex was related to ...weaker preparatory suppression.•Motor excitability appears as a valuable read-out of upstream cognitive processes.
Inhibitory control underlies the ability to inhibit inappropriate responses and involves processes that suppress motor excitability. Such motor modulatory effect has been largely described during action preparation but very little is known about the neural circuit responsible for its implementation. Here, we addressed this point by studying the degree to which the extent of preparatory suppression relates to brain morphometry. We investigated this relationship in patients suffering from severe alcohol use disorder (AUD) because this population displays an inconsistent level of preparatory suppression and major structural brain damage, making it a suitable sample to measure such link. To do so, 45 detoxified patients underwent a structural magnetic resonance imaging (MRI) and performed a transcranial magnetic stimulation (TMS) experiment, in which the degree of preparatory suppression was quantified. Besides, behavioral inhibition and trait impulsivity were evaluated in all participants. Overall, whole-brain analyses revealed that a weaker preparatory suppression was associated with a decrease in cortical thickness of a medial prefrontal cluster, encompassing parts of the anterior cingulate cortex and superior-frontal gyrus. In addition, a negative association was observed between the thickness of the supplementary area (SMA)/pre-SMA and behavioral inhibition abilities. Finally, we did not find any significant correlation between preparatory suppression, behavioral inhibition and trait impulsivity, indicating that they represent different facets of inhibitory control. Altogether, the current study provides important insight on the neural regions underlying preparatory suppression and allows highlighting that the excitability of the motor system represents a valuable read-out of upstream cognitive processes.
Obsessive compulsive disorder (OCD) and Gilles de la Tourette syndrome (GTS) are neurodevelopmental disorders characterized by difficulties in controlling intrusive thoughts (obsessions) and ...undesired actions (tics), respectively. Both conditions have been associated with abnormal inhibition but a tangible deficit of inhibitory control abilities is controversial in GTS.
Here, we examined a 25 years-old male patient with severe OCD symptoms and a mild form of GTS, where impairments in motor control were central. Transcranial magnetic stimulation (TMS) was applied over the primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) during four experimental sessions, allowing us to assess the excitability of motor intracortical circuitry at rest as well as the degree of MEP suppression during action preparation, a phenomenon thought to regulate movement initiation.
When tested for the first time, the patient presented a decent level of MEP suppression during action preparation, but he exhibited a lack of intracortical inhibition at rest, as evidenced by reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI). Interestingly, the patient's symptomatology drastically improved over the course of the sessions (reduced obsessions and tics), coinciding with feedback given on his good motor control abilities. These changes were reflected in the TMS measurements, with a significant strengthening of intracortical inhibition (SICI and LICI more pronounced than previously) and a more selective tuning of MEPs during action preparation; MEPs became even more suppressed, or selectively facilitated depending on the behavioral condition in which they we probed.
This study highlights the importance of better understanding motor inhibitory mechanisms in neurodevelopmental disorders and suggests a biofeedback approach as a potential novel treatment.
A lack of inhibitory control appears to contribute to the development and maintenance of addictive disorders. Among the mechanisms thought to assist inhibitory control, an increasing focus has been ...drawn on the so-called preparatory suppression, which refers to the drastic suppression observed in the motor system during action preparation. Interestingly, deficient preparatory suppression has been reported in alcohol use disorders. However, it is currently unknown whether this deficit also concerns behavioral, substance-free, addictions, and thus whether it might represent a vulnerability factor common to both substance and behavioral addictive disorders. To address this question, neural measures of preparatory suppression were obtained in gambling disorder patients (GDPs) and matched healthy control subjects. To do so, single-pulse transcranial magnetic stimulation was applied over the left and the right motor cortex to elicit motor-evoked potentials (MEPs) in both hands when participants were performing a choice reaction time task. In addition, choice and rapid response impulsivity were evaluated in all participants, using self-report measures and neuropsychological tasks. Consistent with a large body of literature, the MEP data revealed that the activity of the motor system was drastically reduced during action preparation in healthy subjects. Surprisingly, though, a similar MEP suppression was observed in GDPs, indicating that those subjects do not globally suffer from a deficit in preparatory suppression. By contrast, choice impulsivity was higher in GDPs than healthy subjects, and a higher rapid response impulsivity was found in the more severe forms of GD. Altogether, those results demonstrated that although some aspects of inhibitory control are impaired in GDPs, these alterations do not seem to concern preparatory suppression. Yet, the profile of individuals suffering of a GD is very heterogeneous, with only part of them presenting an impulsive disposition, such as in patients with alcohol use disorders. Hence, a lack of preparatory suppression may be only shared by this sub-type of addicts, an interesting issue for future investigation.
Using instructed-delay choice reaction time (RT) paradigms, many previous studies have shown that the motor system is transiently inhibited during response preparation: motor-evoked potentials (MEPs) ...elicited by transcranial magnetic stimulation (TMS) over the primary motor cortex are typically suppressed during the delay period. This effect has been observed in both selected and non-selected effectors, although MEP changes in selected effectors have been more inconsistent across task versions. Here, we compared changes in MEP amplitudes in three different variants of an instructed-delay choice RT task. All variants required participants to choose between left and right index finger movements but the responses were either provided "in the air" (Variant 1), on a regular keyboard (Variant 2), or on a response device designed to control from premature responses (Variant 3). The task variants also differed according to the visual layout (more concrete in Variant 3) and depending on whether participants received a feedback of their performance (absent in Variant 1). Behavior was globally comparable between the three variants of the task although the propensity to respond prematurely was highest in Variant 2 and lowest in Variant 3. MEPs elicited in a non-selected hand were similarly suppressed in the three variants of the task. However, significant differences emerged when considering MEPs elicited in the selected hand: these MEPs were suppressed in Variants 1 and 3 whereas they were often facilitated in Variant 2, especially in the right dominant hand. In conclusion, MEPs elicited in selected muscles seem to be more sensitive to small variations to the task design than those recorded in non-selected effectors, probably because they reflect a complex combination of inhibitory and facilitatory influences on the motor output system. Finally, the use of a standard keyboard seems to be particularly inappropriate because it encourages participants to respond promptly with no means to control for premature responses, probably increasing the relative amount of facilitatory influences at the time motor inhibition is probed.
•Excessive preparatory excitatory drive is associated with hazardous drinking.•Deficient preparatory inhibitory drive only concerns severe alcohol use disorders.•Immersion in a virtual ...alcohol-related environment can increase craving.•Craving does not affect the strength of preparatory excitatory or inhibitory drive.
Action preparation relies on the operation of control processes that modulate the excitability of the corticospinal tract. On the one hand, excitatory processes prepare the motor system for the forthcoming response; the stronger these influences, the stronger the tendency to act. On the other hand, inhibitory influences allow to suppress inappropriate actions and, more generally, to ensure some sort of impulse control. Because an impairment in these processes could foster inappropriate drinking behavior, the present study aimed at evaluating the motor correlates of such excitatory and inhibitory influences in non-treatment seeking heavy drinkers (HDs) and inpatients suffering from severe alcohol use disorder (SAUDs). Besides, as cue-elicited craving might further alter these processes, we also assessed the impact of an alcohol-related exposure. To do so, 15 healthy controls (HCs), 15 HDs and 15 SAUDs performed a choice reaction time task after having been immersed in a neutral or an alcohol-related environment, using virtual reality videos. Importantly, single-pulse transcranial magnetic stimulation was applied over the left and the right primary motor cortex during the task to elicit motor-evoked potentials in a set of hand muscles allowing us to specifically probe the impact of excitatory and inhibitory processes on motor activity. Our data indicate that excitatory influences are particularly high in both HDs and SAUDs, especially in the dominant hand, an effect that was not observed in HCs. By contrast, inhibitory influences were found to be perfectly normal in HDs, while they were lacking in SAUDs. Furthermore, the alcohol-related exposure enhanced the level of self-reported craving, but this effect only arose in HDs and did not significantly alter the strength of excitatory and inhibitory influences. Overall, although these results have to be taken with caution due to the small sample sizes, this study suggests that enhanced excitatory processes characterize both HDs and SAUDs, while weaker inhibitory influences only concern SAUDs. Hence, an abnormally strong tendency to act could represent a common feature of hazardous drinking, leading individuals to excessive alcohol consumption, whereas deficient impulse control would be a hallmark of more severe forms of AUD, potentially due to the chronic neurotoxic effects of alcohol. Finally, although an alcohol-related exposure does not seem to affect excitatory and inhibitory processes at play during action preparation per se, future works should evaluate changes in corticospinal excitability during the preparation of responses specifically targeting alcohol-related cues.
Abstract 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
Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral ...sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal‐ or ethanol‐evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol‐sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol‐sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol‐sensitized mice. Finally, ethanol superfusion (10–100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol‐sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol.
The present study tested whether in vivo ethanol locomotor sensitization correlates with changes in either basal or ethanol‐evoked firing rates of dopamine neurons in vitro in mice. Higher spontaneous basal firing rates of dopamine neurons were observed in ethanol sensitized mice relative to control mice, but without correlations with the behavioral effects. Ethanol‐evoked firing rates of dopamine neurons were of higher magnitude in ethanol sensitized mice. Furthermore, this sensitization of dopamine neuron activity was significantly correlated with ethanol behavioral sensitization.
Background
Anxiety and depression are psychopathological states frequently co‐occurring with severe alcohol use disorder (SAUD). These symptoms generally disappear with abstinence but may persist in ...some patients, increasing the relapse risk.
Methods
The cerebral cortex thickness of 94 male patients with SAUD was correlated with symptoms of depression and anxiety, both measured at the end (2–3 weeks) of the detoxification treatment. Cortical measures were obtained using surface‐based morphometry implemented with Freesurfer.
Results
Depressive symptoms were associated with reduced cortical thickness in the superior temporal gyrus of the right hemisphere. Anxiety level was correlated with lower cortical thickness in the rostral middle frontal region, inferior temporal region, and supramarginal, postcentral, superior temporal, and transverse temporal regions of the left hemisphere, as well as with a large cluster in the middle temporal region of the right hemisphere.
Conclusions
At the end of the detoxification stage, the intensity of depressive and anxiety symptoms is inversely associated with the cortical thickness of regions involved in emotions‐related processes, and the persistence of the symptoms could be explained by these brain deficits.
At the end of the detoxification stage in men with severe alcohol use disorders, the intensity of depressive and anxiety symptoms is inversely associated with the cortical thickness of regions involved in emotions‐related processes, and the persistence of the symptoms despite of alcohol cessation could be explained by these brain deficits.
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 preparatory inhibition may assist action selection.
•Addressed the debated idea that preparatory inhibition assists action selection.•Compared MEPs in simple and choice RT tasks (no catch, no delay).•Detected preparatory suppression of MEPs, although weaker than usual.•Observed a more consistent suppression of MEPs in the choice than simple setting.•Provided support for action selection hypothesis.
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