Children's Preferences for Oral Dosage Forms and Their Involvement in Formulation Research via EPTRI (European Paediatric Translational Research Infrastructure).

The paucity of evidence-based data on formulation characteristics preferred by the children is known to limit the design of tailored paediatric dosage forms. The European Paediatric Translational Research Infrastructure (EPTRI) commissioned a study to evaluate children's dosage forms perceived preferences in some European countries and explore the feasibility of using the young persons advisory groups (YPAGs) to involve children in formulation research. An online, age-adapted survey was developed and translated into six languages. The survey link was disseminated across seven European countries: Albania, Italy, the Netherlands, and Dutch-speaking part of Belgium, Romania, Spain, and the United Kingdom. Respondents' (n = 1172) perceived preferences for oral dosage forms primarily differed based on age, health status, and experience. Conventional dosage forms, i.e., liquid (35%), tablets (19%), and capsules (14%), were the most selected. Liquid was widely selected by children less than 12 years and by those healthy and taking medicines rarely. Monolithic solid forms were mostly chosen by adolescents and by children with a chronic disease taking medicines frequently. There was a clear lack of familiarity with more novel dosage forms (e.g., orodispersible films and granules). Noteworthy, granules were not appreciated, particularly by adolescents (52.8%). To rationalise the creation of paediatric formulations, it is important to involve children as active stakeholders and to apply tools assessing children's perspectives on medicines to inform acceptable dosage form development from the start.

Preparing for hard times: Scalp and intracranial physiological signatures of proactive cognitive control.

Based on reward and difficulty information, people can strategically adjust proactive cognitive control. fMRI research shows that motivated proactive control is implemented through fronto-parietal control networks that are triggered by reward and difficulty cues. Here, we investigate electrophysiological signatures of proactive control. Previously, the contingent negative variation (CNV) in the ERPs and oscillatory power in the theta (4-8 Hz) and alpha band (8-14 Hz) have been suggested as signatures of control implementation. However, experimental designs did not always separate control implementation from motor preparation. Critically, we used a mental calculation task to investigate effects of proactive control implementation on the CNV and on theta and alpha power, in absence of motor preparation. In the period leading up to task onset, we found a more negative CNV, increased theta power, and decreased alpha power for hard versus easy calculations, showing increased proactive control implementation when a difficult task was expected. These three measures also correlated with behavioral performance, both across trials and across subjects. In addition to scalp EEG in healthy participants, we collected intracranial local field potential recordings in an epilepsy patient. We observed a slow-drift component that was more pronounced for hard trials in a hippocampal location, possibly reflecting task-specific preparation for hard mental calculations. The current study thus shows that difficulty information triggers proactive control in absence of motor preparation and elucidates its neurophysiological signatures.

Decoding Steady-State Visual Evoked Potentials From Electrocorticography.

We report on a unique electrocorticography (ECoG) experiment in which Steady-State Visual Evoked Potentials (SSVEPs) to frequency- and phase-tagged stimuli were recorded from a large subdural grid covering the entire right occipital cortex of a human subject. The paradigm is popular in EEG-based Brain Computer Interfacing where selectable targets are encoded by different frequency- and/or phase-tagged stimuli. We compare the performance of two state-of-the-art SSVEP decoders on both ECoG- and scalp-recorded EEG signals, and show that ECoG-based decoding is more accurate for very short stimulation lengths (i.e., less than 1 s). Furthermore, whereas the accuracy of scalp-EEG decoding benefits from a multi-electrode approach, to address interfering EEG responses and noise, ECoG decoding enjoys only a marginal improvement as even a single electrode, placed over the posterior part of the primary visual cortex, seems to suffice. This study shows, for the first time, that EEG-based SSVEP decoders can in principle be applied to ECoG, and can be expected to yield faster decoding speeds using less electrodes.

Representation of steady-state visual evoked potentials elicited by luminance flicker in human occipital cortex: An electrocorticography study.

Despite the widespread use of steady-state visual evoked potentials (SSVEPs) elicited by luminance flicker in clinical and research settings, their spatial and temporal representation in the occipital cortex largely remain elusive. We performed intracranial-EEG recordings in response to targets flickering at frequencies from 11 to 15 Hz using a subdural electrode grid covering the entire right occipital cortex of a human subject, and we were able to consistently locate the gazed stimulus frequency at the posterior side of the primary visual cortex (V1). Peripheral flickering, undetectable in scalp-EEG, elicited activations in the interhemispheric fissure at locations consistent with retinotopic maps. Both foveal and peripheral activations spatially coincided with activations in the high gamma band. We detected localized alpha synchronization at the lateral edge of V2 during stimulation and transient post-stimulation theta band activations at the posterior part of the occipital cortex. Scalp-EEG exhibited only a minor occipital post-stimulation theta activation, but a strong transient frontal activation.

Reduced distractor interference during vagus nerve stimulation.

Suppressing irrelevant information in decision making is an essential everyday skill. We studied whether this ability could be improved in epileptic patients during vagus nerve stimulation (VNS). VNS is known to increase norepinephrine (NE) in the brain. NE is thought to improve several aspects of cognitive control, including the suppression of irrelevant information. Nineteen epileptic VNS patients executed the Eriksen flanker task twice, both during on and off stimulation. Distractor interference was indexed by the congruency effect, a standard empirical marker of cognitive control. We found a reduced congruency effect during stimulation, which indicates an improved ability to suppress distractor interference. This effect was only found in patients that are clinically determined VNS-responders (n = 10). As VNS increases NE in VNS-responders, our finding suggests a beneficial role of NE in cognitive control. At the same time, it suggests that VNS does not only reduce seizure frequency in epileptic patients, but also improves cognitive control.

EEG Derived Brain Activity Reflects Treatment Response from Vagus Nerve Stimulation in Patients with Epilepsy.

The mechanism of action of vagus nerve stimulation (VNS) is yet to be elucidated. To that end, the effects of VNS on the brain of epileptic patients were studied. Both when VNS was switched "On" and "Off", the brain activity of responders (R, seizure frequency reduction of over 50%) was compared to the brain activity of nonresponders (NR, seizure frequency reduction of less than 50%). Using EEG recordings, a significant increase in P300 amplitude for R and a significant decrease in P300 amplitude for NR were found. We found biomarkers for checking the efficacy of VNS with accuracy up to 94%. The results show that P300 features recorded in nonmidline electrodes are better P300 biomarkers for VNS efficacy than P300 features recorded in midline electrodes. Using source localization and connectivity analyses, the activity of the limbic system, insula and orbitofrontal cortex was found to be dependent on VNS switched "On" versus "Off" or patient group (R versus NR). The results suggest an important role for these areas in the mechanism of action of VNS, although a larger patient study should be done to confirm the findings.

The effect of vagus nerve stimulation on response inhibition.

In the current study, we explored whether vagus nerve stimulation (VNS) in patients with epilepsy, which is believed to increase norepinephrine (NE) levels via activation of the locus coeruleus, would positively affect response inhibition. Moreover, we tried to identify the dynamics of the underlying neural processes by investigating event-related potentials (ERPs) and pupil size. Patients performed a stop-signal task once when stimulation was switched on and once when it was switched off. We found a correlational pattern suggesting that patients who clinically benefit more from VNS treatment also show a larger behavioral advantage, in terms of faster response inhibition, when the vagus nerve is being stimulated. Event-related potential (ERP) results suggested more pronounced reactive inhibition when stimulation was switched on, independent of the individual amount of seizure reduction. Transient go-locked pupil size was increased from go trials to successful stop trials to unsuccessful stop trials but without displaying a clear VNS effect, which however, might relate to limited sensitivity. We conclude that VNS likely has a positive effect on response inhibition, at least in patients with epilepsy that benefit clinically from the treatment, presumably relating to enhancements of response-inhibition mechanisms and, therefore, identify enhanced response inhibition as a possible cognitive benefit of VNS.

A Preclinical Study of Laryngeal Motor-Evoked Potentials as a Marker Vagus Nerve Activation.

Vagus nerve stimulation (VNS) is a treatment for refractory epilepsy and depression. Previous studies using invasive recording electrodes showed that VNS induces laryngeal motor-evoked potentials (LMEPs) through the co-activation of the recurrent laryngeal nerve and subsequent contractions of the laryngeal muscles. The present study investigates the feasibility of recording LMEPs in chronically VNS-implanted rats, using a minimally-invasive technique, to assess effective current delivery to the nerve and to determine optimal VNS output currents for vagal fiber activation. Three weeks after VNS electrode implantation, signals were recorded using an electromyography (EMG) electrode in the proximity of the laryngeal muscles and a reference electrode on the skull. The VNS output current was gradually ramped up from 0.1 to 1.0 mA in 0.1 mA steps. In 13/27 rats, typical LMEPs were recorded at low VNS output currents (median 0.3 mA, IQR 0.2-0.3 mA). In 11/27 rats, significantly higher output currents were required to evoke electrophysiological responses (median 0.7 mA, IQR 0.5-0.7 mA, p < 0.001). The latencies of these responses deviated significantly from LMEPs (p < 0.05). In 3/27 rats, no electrophysiological responses to simulation were recorded. Minimally invasive LMEP recordings are feasible to assess effective current delivery to the vagus nerve. Furthermore, our results suggest that low output currents are sufficient to activate vagal fibers.

Event-related potentials reveal preserved attention allocation but impaired emotion regulation in patients with epilepsy and comorbid negative affect.

Patients with epilepsy have a high prevalence of comorbid mood disorders. This study aims to evaluate whether negative affect in epilepsy is associated with dysfunction of emotion regulation. Event-related potentials (ERPs) are used in order to unravel the exact electrophysiological time course and investigate whether a possible dysfunction arises during early (attention) and/or late (regulation) stages of emotion control. Fifty epileptic patients with (n = 25) versus without (n = 25) comorbid negative affect plus twenty-five matched controls were recruited. ERPs were recorded while subjects performed a face- or house-matching task in which fearful, sad or neutral faces were presented either at attended or unattended spatial locations. Two ERP components were analyzed: the early vertex positive potential (VPP) which is normally enhanced for faces, and the late positive potential (LPP) that is typically larger for emotional stimuli. All participants had larger amplitude of the early face-sensitive VPP for attended faces compared to houses, regardless of their emotional content. By contrast, in patients with negative affect only, the amplitude of the LPP was significantly increased for unattended negative emotional expressions. These VPP results indicate that epilepsy with or without negative affect does not interfere with the early structural encoding and attention selection of faces. However, the LPP results suggest abnormal regulation processes during the processing of unattended emotional faces in patients with epilepsy and comorbid negative affect. In conclusion, this ERP study reveals that early object-based attention processes are not compromised by epilepsy, but instead, when combined with negative affect, this neurological disease is associated with dysfunction during the later stages of emotion regulation. As such, these new neurophysiological findings shed light on the complex interplay of epilepsy with negative affect during the processing of emotional visual stimuli and in turn might help to better understand the etiology and maintenance of mood disorders in epilepsy.

The P3 event-related potential is a biomarker for the efficacy of vagus nerve stimulation in patients with epilepsy.

Currently, the mechanism of action of vagus nerve stimulation (VNS) is not fully understood, and it is unclear which factors determine a patient's response to treatment. Recent preclinical experiments indicate that activation of the locus coeruleus noradrenergic system is critical for the antiepileptic effect of VNS. This study aims to evaluate the effect of VNS on noradrenergic signaling in the human brain through a noninvasive marker of locus coeruleus noradrenergic activity: the P3 component of the event-related potential. We investigated whether VNS differentially modulates the P3 component in VNS responders versus VNS nonresponders. For this purpose, we recruited 20 patients with refractory epilepsy who had been treated with VNS for at least 18 months. Patients were divided into 2 groups with regard to their reduction in mean monthly seizure frequency: 10 responders (>50 %) and 10 nonresponders (≤50 %). Two stimulation conditions were compared: VNS OFF and VNS ON. In each condition, the P3 component was measured during an auditory oddball paradigm. VNS induced a significant increase of the P3 amplitude at the parietal midline electrode, in VNS responders only. In addition, logistic regression analysis showed that the increase of P3 amplitude can be used as a noninvasive indicator for VNS responders. These results support the hypothesis that activation of the locus coeruleus noradrenergic system is associated with the antiepileptic effect of VNS. Modulation of the P3 amplitude should be further investigated as a noninvasive biomarker for the therapeutic efficacy of VNS in patients with refractory epilepsy.