Search

The contribution of brain regions to visuospatial abilities according to sex differences and gender identity is inconsistently described. One potential explaining factor may be the different tasks employed requiring a variable load of working memory and other cognitive resources. Here we asked to 20 cis and 20 transgender participants to undergo functional Magnetic Resonance Imaging during performance of a judgement line of orientation test that was adapted to explore the basic visuospatial processing while minimizing the working memory load. We show that V1 activation may be viewed as a brain area with enhanced activation in males, regardless of participants’ gender identity. On its turn, gender identity exclusively influences the visuospatial processing of extrastriate visual areas (V5) in women with gender dysphoria. They showed enhanced V5 activation and an increased functional connectivity between V5 and V1. Overall our neuroimaging results suggest that the basic visuospatial abilities are associated with different activations pattern of cortical visual areas depending on the sex assigned at birth and gender identity.

Linguistic tasks facilitate corticospinal excitability as revealed by increased motor evoked potential (MEP) induced by transcranial magnetic stimulation (TMS) in the dominant hand. This modulation of the primary motor cortex (M1) excitability may reflect the relationship between speech and gestures. It is conceivable that in healthy individuals who use a sign language this cortical excitability modulation could be rearranged. The aim of this study was to evaluate the effect of spoken language tasks on M1 excitability in a group of hearing signers. Ten hearing Italian Sign Language (LIS) signers and 16 non-signer healthy controls participated. Single-pulse TMS was applied to either M1 hand area at the baseline and during different tasks: (i) reading aloud, (ii) silent reading, (iii) oral movements, (iv) syllabic phonation and (v) looking at meaningless non-letter strings. Overall, M1 excitability during the linguistic and non-linguistic tasks was higher in LIS group compared to the control group. In LIS group, MEPs were significantly larger during reading aloud, silent reading and non-verbal oral movements, regardless the hemisphere. These results suggest that in hearing signers there is a different modulation of the functional connectivity between the speech-related brain network and the motor system.

The phenomenon of near-death experiences (NDE), intense and profound subjective experiences, is characterized by the perception of being in a different dimension from the ordinary one, of having abandoned one’s body and, with it, the space-time dimension of the physical world. The term NDE has been used to indicate similar experiences that occurred in very different clinical conditions, namely cardiac arrest, coma, fainting, use of psychotropic substances, etc. In what follows will be considered only experiences taking place in conditions of proximity to death. The phenomenon will be discussed comparing elements most commonly present in NDEs of Western subjects with those reported by subjects from other cultures. The various near-death experiences will be discussed in according to the contents reported and the ways in which they occurred. Finally, the state of coma was considered as a near-death condition under the assumption of death as a process.

This study aimed to investigate the effect of different sport environments (open-and closed-skill sports) on proactive and reactive inhibitory processes as two distinct components of motor inhibition. A mouse-tracking procedure was employed to compare behavioral performance among three groups of participants (tennis players, swimmers and non-athletes) in non-sport-specific cued Go/No-Go (GNG) and Stop Signal Task (SST), which mainly engage proactive and reactive inhibitory control, respectively. Reaction times (RTs), inhibitory failures, and Stop Signal Reaction Times (SSRTs) were measured. To investigate dynamic aspects of inhibitory control, movement trajectories classified as one-shot (absence of trajectory alteration reflected in a steep slope) or non-one-shot (non-linear/multipeaked trajectory, with one or multiple corrections) were analyzed and compared among groups. Results showed no group differences in RTs in Go/No-Go and Stop conditions. SSRTs were significant shorter for the athletes than non-athletes in SST, but no differences emerged for inhibitory failures in cued GNG. During inhibitory failures athletes showed higher proportion of non-one-shot movements than non-athletes. Higher proportion of non-one-shot profiles was observed in cued GNG compared to SST. Finally, no differences between open-and closed-skilled athletes were found in both tasks. Our findings suggest that both proactive and reactive inhibitory controls do benefit from sport practice, but open-and closed-skill sports do not differ in influencing inhibitory processes. Movement profile analysis could be a promising, complementary behavioral analysis to integrate for more fine-grained evaluation and differentiation of inhibitory motor control in athletes, specifically when using GNG tasks.

This study aimed to investigate the effect of different sport environments (open-and closed-skill sports) on proactive and reactive inhibitory processes as two distinct components of motor inhibition. A mouse-tracking procedure was employed to compare behavioral performance among three groups of participants (tennis players, swimmers and non-athletes) in non-sport-specific cued Go/No-Go (GNG) and Stop Signal Task (SST), which mainly engage proactive and reactive inhibitory control, respectively. Reaction times (RTs), inhibitory failures, and Stop Signal Reaction Times (SSRTs) were measured. To investigate dynamic aspects of inhibitory control, movement trajectories classified as one-shot (absence of trajectory alteration reflected in a steep slope) or non-one-shot (non-linear/multipeaked trajectory, with one or multiple corrections) were analyzed and compared among groups. Results showed no group differences in RTs in Go/No-Go and Stop conditions. SSRTs were significant shorter for the athletes than non-athletes in SST, but no differences emerged for inhibitory failures in cued GNG. During inhibitory failures athletes showed higher proportion of non-one-shot movements than non-athletes. Higher proportion of non-one-shot profiles was observed in cued GNG compared to SST. Finally, no differences between open-and closed-skilled athletes were found in both tasks. Our findings suggest that both proactive and reactive inhibitory controls do benefit from sport practice, but open-and closed-skill sports do not differ in influencing inhibitory processes. Movement profile analysis could be a promising, complementary behavioral analysis to integrate for more fine-grained evaluation and differentiation of inhibitory motor control in athletes, specifically when using GNG tasks.

Background: The Token Test (TT) is widely used to examine comprehension disorders in aphasic patients, but abilities other than language may affect a patient’s performance. This study aims to explore the correlation between the TT subtest performances and the performances in extra-linguistic cognitive areas in a cohort of patients from the Intensive Rehabilitation Post-Stroke (RIPS) study with a first, right hemisphere stroke and without aphasia, prospectively enrolled at admission to intensive inpatient post-acute rehabilitation. Methods: The patients were administered the TT (50-item version), the forward and backward digit span (DST), and the Montreal Cognitive Assessment (MoCA). Spearman’s partial correlations adjusted by age were used to evaluate the association between the number of errors in the TT and the other tests’ corrected scores. Results: Of the 37 patients enrolled in this study, 29.7% made 3–11 errors on the TT, 27.0% more than 11 errors, mostly in parts IV and V. The forward and backward digit span scores showed correlations with errors in part V of the TT (r = −0.408, p = 0.013; r = −0.307, p = 0.027). The errors in part IV of the TT presented a correlation with a forward digit span too (r = −0.394, p = 0.017). With respect to MoCA domains, executive functioning, and orientation were related to the TT part V errors (r = −0.468, p = 0.007; r = −0.499, p = 0.003). The orientation also correlated with the TT part III (r = −0.504, p = 0.002). Conclusion: Our findings show that the TT performances in patients with right hemisphere stroke and without aphasia are related to impairments in auditory–verbal span/auditory working memory mostly for TT scores on subpart V as measured by the DST and to executive function and orientation, as measured by the MoCA subtests.

In patients with Parkinson’s disease (PD), impulsivity is still a matter of investigation. It has been hypothesized that impulsive personality traits may favour impulse control disorder (ICD) onset during dopaminergic therapy. In healthy subjects, a relationship between the awareness of motor intention and impulsive personality traits assessed by the Barratt impulsivity scale (BIS-11) has been reported. The aim of this study was to evaluate the relationship between the awareness of voluntary action and impulsivity traits in PD. Twenty-eight PD patients (stages I-III on the Hoehn and Yahr scale) underwent an impulsivity trait assessment by the BIS-11 scale and a task based on the Libet’s clock. Participants were requested to perform a self-initiated movement and report the time they first feel their intention to move (W-judgement) or the time of the actual movement (M-judgement). In patients with higher BIS-11 scores, the time lag between the W-judgement and the actual movement was significantly lower than in patients with lower BIS-11. No difference emerged in the M-judgement. Data suggest that also in PD patients, the impulsive personality trait is related to a “delayed” awareness of motor intention and therefore to a shorter interval to allow a conscious “veto” of the impending action. Characterization of the temporal profile of awareness of motor intention could prove useful in identifying PD patients at risk of developing ICDs during dopaminergic treatment.

Neurophysiological studies suggest that music reading facilitates sensorimotor cortex. The aim of this study was to evaluate (1) whether in pianists, reading notes in bass and treble clef selectively enhances right and left primary motor cortex (M1) excitability; and (2) whether reading notes played with the thumb or little finger selectively modulates the excitability of specific muscles. Twenty musicians (11 pianists, 9 non-pianists) participated. Transcranial magnetic stimulation (TMS) was applied while subjects read the bass or the treble clef of sheets music and during the observation of a blank staff (baseline). When pianists read the treble clef, the excitability of the left M1 was higher compared to that recorded in the right M1. Moreover, in the treble clef condition motor evoked potentials (MEPs) induced by TMS of the left M1 were higher when pianists read notes to be played with the 5° finger (little finger) with respect to 1° finger (thumb) notes, whereas in the bass clef condition TMS of the right M1 induced higher MEPs for 1° finger note compared to 5° finger notes. No significant modulation was observed in non-pianists. These data support the view that music reading may induce specific inter- and intra-hemispheric modulation of the motor cortex excitability.

Previous studies have evidenced cognitive difficulties across various domains in Type 1 Diabetes Mellitus (T1DM) children, but the implicit memory system has not yet been systematically explored.Taking into account that the interplay between memory and perception may be modulated by the semantic category of the stimuli and their salience, we explored explicit and implicit memory using both object and food stimuli to verify whether for T1DM children there is a feebleness in performing the function of memory as a function of the stimuli used.Eighteen T1DM children and 47 healthy children performed an explicit recognition task in which they were requested to judge whether the presented image had already been shown ("old") or not ("new") and an identification priming task in which they were asked to name new and old pictures presented at nine ascending levels of spatial filtering.Results did not reveal any differences between controls and T1DM children in the explicit memory recognition task, whereas some differences between the two groups were found in the identification priming task. In T1DM children, the priming effect was observed only for food images.The dissociation between implicit and explicit memory observed in children with diabetes seems to be modulated by the category of the stimuli, and these results underscore the relevance of taking into account this variable when exploring cognitive functions.

Participants of clinical trials who receive a placebo treatment often report a variety of adverse events, sometimes called nocebo effects. The reason why these adverse events occur is not clear, and understanding the underlying mechanisms represents a challenge that is likely to improve the interpretation of clinical trials as well as medical practice. Here, we studied 192 healthy subjects who received placebo oxygen through a mask after reading (READ) or not reading (NO-READ) a list of possible adverse events of oxygen breathing: headache, chest pain, abdominal pain, and cough. The whole hypothalamus-pituitary-adrenal axis was assessed just before and right after placebo breathing by measuring the hypothalamic corticotropin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol (COR). In addition, both state and trait anxiety were assessed. We found that 64.5% of the NO-READ group reported no adverse events, 30.2% had one, and only 5.2% had two adverse events. In contrast, only 20.8% of the READ group reported no adverse events, whereas 1, 2, 3, and 4 adverse events were reported with a frequency of 21.8%, 19.8%, 19.8%, and 17.7%, respectively. In addition, when the READ group reported three and four adverse events, CRH, ACTH, and COR were significantly increased compared to the NO-READ group, along with an increase in state anxiety scores. These data indicate that hypothalamic-pituitary-adrenal activity and state anxiety are increased in those subjects who report many adverse events after reading a list of adverse events, thus highlighting a possible neuroendocrine mechanism after placebo administration.

Individual abilities in face recognition (good versus bad recognizers) were explored by means of event-related potentials (ERPs). The adaptation response profile of the N170 component to whole faces, eyes and mouths was used in order to highlight the crucial role of individual abilities in identity repetition processes for unfamiliar faces. The main point of this study is to underline the importance of characterizing the performance (bad or good) of the participants and to show that behaviorally selected groups might reveal neural differences. Good recognizers showed selective right hemisphere N170 repetition effects for whole faces and not for features. On the contrary, bad recognizers showed a general repetition effect not specifically related to faces and more pronounced processing for features. These findings suggest a different contribution of holistic and featural analysis in bad and good performers. In conclusion, we propose that the N170 might be used as a tool to tease apart face encoding processes as a function of individual differences.

In patients with Parkinson's disease (PD), impulsivity is still a matter of investigation. It has been hypothesized that impulsive personality traits may favour impulse control disorder (ICD) onset during dopaminergic therapy. In healthy subjects, a relationship between the awareness of motor intention and impulsive personality traits assessed by the Barratt impulsivity scale (BIS-11) has been reported. The aim of this study was to evaluate the relationship between the awareness of voluntary action and impulsivity traits in PD.Twenty-eight PD patients (stages I-III on the Hoehn and Yahr scale) underwent an impulsivity trait assessment by the BIS-11 scale and a task based on the Libet's clock. Participants were requested to perform a self-initiated movement and report the time they first feel their intention to move (W-judgement) or the time of the actual movement (M-judgement).In patients with higher BIS-11 scores, the time lag between the W-judgement and the actual movement was significantly lower than in patients with lower BIS-11. No difference emerged in the M-judgement.Data suggest that also in PD patients, the impulsive personality trait is related to a "delayed" awareness of motor intention and therefore to a shorter interval to allow a conscious "veto" of the impending action. Characterization of the temporal profile of awareness of motor intention could prove useful in identifying PD patients at risk of developing ICDs during dopaminergic treatment.

Cognitive control is a critical feature in adapting our behavior to environmental and internal demands with two types of inhibition having been identified, namely the proactive and the reactive. Aiming to shed light on their respective neural correlates, we decided to focus on the cerebral activity before or after presentation of the target demanding a subject’s stop as a way to separate the proactive from the reactive components associated with the tasks. Accordingly, we performed three Activation Likelihood Estimation (ALE) meta-analyses of fMRI studies exploring proactive and reactive inhibitory phases of cognitive control. For this purpose, we searched for fMRI studies investigating brain activity preceding or following target stimuli. Eight studies (291 subjects, 101 foci) were identified for the proactive analysis. Five of these studies and those previously analyzed by others (348 subjects, 199 foci) were meta-analyzed to explore the neural correlates of reactive inhibition. Overall, our results showed different networks for the two inhibitory components. Notably, we observed a contiguity between areas in the right inferior frontal gyrus pertaining to proactive inhibition and in the right middle frontal gyrus regarding reactive inhibition. These neural correlates allow proposal of a new comprehensive model of cognitive control.

Event-related potentials (ERPs) are obtained from the electroencephalogram (EEG) or the magnetoencephalogram (MEG, event-related fields (ERF)), extracting the activity that is time-locked to an event. Despite the potential utility of ERP/ERF in cognitive domain, the clinical standardization of their use is presently undefined for most of procedures. The aim of the present review is to establish limits and reliability of ERP medical application, summarize main methodological issues, and present evidence of clinical application and future improvement. The present section of the review focuses on well-standardized ERP methods, including P300, Contingent Negative Variation (CNV), Mismatch Negativity (MMN), and N400, with a chapter dedicated to laser-evoked potentials (LEPs). One section is dedicated to proactive preparatory brain activity as the Bereitschaftspotential and the prefrontal negativity (BP and pN). The P300 and the MMN potentials have a limited but recognized role in the diagnosis of cognitive impairment and consciousness disorders. LEPs have a well-documented usefulness in the diagnosis of neuropathic pain, with low application in clinical assessment of psychophysiological basis of pain. The other ERP components mentioned here, though largely applied in normal and pathological cases and well standardized, are still confined to the research field. CNV, BP, and pN deserve to be largely tested in movement disorders, just to explain possible functional changes in motor preparation circuits subtending different clinical pictures and responses to treatments.

Emotional contexts affect memory processes. However, the impact of contextual priming as a function of the emotional valence on the recall of neutral information is not fully understood. The aim of the present study was to evaluate how a conditioning of emotional context during encoding may influence the subsequent memory of otherwise neutral materials in a well-established phenomenon as the serial position effect. Participants performed a free recall task for neutral words in three conditions: (i) word list alone; (ii) word list coupled with positive or neutral images; and (iii) word list coupled with negative or neutral images. Images were presented before each word stimulus. In three different experiments, the emotional context during the word list presentation was manipulated separately for primacy and recency clusters, and for the middle words (‘middlecy’). Emotional context affects free recall of neutral stimuli, changing the serial position curve effect across conditions. Namely, emotional images presented in the primacy and recency clusters worsen accuracy, whereas their occurrence in the ‘middlecy’ cluster reduces the oblivion. The present findings show that the typical pattern related to the serial position curve for neutral information can be shaped by the conditioning of emotional context. Findings have implications in medical-legal contexts in the case of the recollection of events with high emotional content.

Response inhibition relies on both proactive and reactive mechanisms that exert a synergic control on goal-directed actions. It is typically evaluated by the go/no-go (GNG) and the stop signal task (SST) with response recording based on the key-press method. However, the analysis of discrete variables (i.e., present or absent responses) registered by key-press could be insufficient to capture dynamic aspects of inhibitory control. Trying to overcome this limitation, in the present study we used a mouse tracking procedure to characterize movement profiles related to proactive and reactive inhibition. A total of fifty-three participants performed a cued GNG and an SST. The cued GNG mainly involves proactive control whereas the reactive component is mainly engaged in the SST. We evaluated the velocity profile from mouse trajectories both for responses obtained in the Go conditions and for inhibitory failures. Movements were classified as one-shot when no corrections were observed. Multi-peaked velocity profiles were classified as non-one-shot. A higher proportion of one-shot movements was found in the SST compared to the cued GNG when subjects failed to inhibit responses. This result suggests that proactive control may be responsible for unsmooth profiles in inhibition failures, supporting a differentiation between these tasks.

Event-related potentials (ERPs) are obtained from the electroencephalogram (EEG) or the magnetoencephalogram (MEG, event-related fields (ERF)), extracting the activity that is time-locked to an event. Despite the potential utility of ERP/ERF in cognitive domain, the clinical standardization of their use is presently undefined for most of procedures. The aim of the present review is to establish limits and reliability of ERP medical application, summarize main methodological issues, and present evidence of clinical application and future improvement. The present section of the review focuses on well-standardized ERP methods, including P300, Contingent Negative Variation (CNV), Mismatch Negativity (MMN), and N400, with a chapter dedicated to laser-evoked potentials (LEPs). One section is dedicated to proactive preparatory brain activity as the Bereitschaftspotential and the prefrontal negativity (BP and pN). The P300 and the MMN potentials have a limited but recognized role in the diagnosis of cognitive impairment and consciousness disorders. LEPs have a well-documented usefulness in the diagnosis of neuropathic pain, with low application in clinical assessment of psychophysiological basis of pain. The other ERP components mentioned here, though largely applied in normal and pathological cases and well standardized, are still confined to the research field. CNV, BP, and pN deserve to be largely tested in movement disorders, just to explain possible functional changes in motor preparation circuits subtending different clinical pictures and responses to treatments.

Background Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique able to transiently modulate brain activity, is surging as one of the most promising therapeutic solutions in many neurological and psychiatric disorders. However, profound limitations exist in current placebo (sham) protocols that limit single- and double-blinding, especially in non-naive subjects. Objective To ensure better blinding and strengthen reliability of tDCS studies and trials, we tested a new optimization algorithm aimed at creating an “active” sham tDCS condition (ActiSham hereafter) capable of inducing the same scalp sensations perceived during real stimulation while preventing currents from reaching the cortex and cause changes in brain excitability. Methods A novel model-based multielectrode technique — optimizing the location and currents of a set of small electrodes placed on the scalp — was used to control the relative amount of current delivered transcranially in real and placebo multichannel tDCS conditions. The presence, intensity and localization of scalp sensations during tDCS was evaluated by means of a specifically designed questionnaire administered to the participants. We compared blinding ratings by directly addressing subjects’ ability to discriminate across conditions for both traditional (Bifocal-tDCS and Sham, using sponge electrodes) and our novel multifocal approach (both real Multifocal-tDCS and ActiSham). Changes in corticospinal excitability were monitored based on Motor Evoked Potentials (MEPs) recorded via concurrent Transcranial Magnetic Stimulation (TMS) and electromyography (EMG). Results Participants perceived Multifocal-tDCS and ActiSham similarly in terms of both localization and intensity of scalp sensations, whereas traditional Bifocal stimulation was rated as more painful and annoying compared to its Sham counterpart. Additionally, differences in scalp localization were reported for active/sham Bifocal-tDCS, with Sham tDCS inducing more widespread itching and burning sensations. As for MEPs amplitude, a main effect of stimulation was found when comparing Bifocal-Sham and ActiSham (F(1,13) = 6.67, p = .023), with higher MEPs amplitudes after the application of Bifocal-Sham. Conclusions Compared to traditional Bifocal-tDCS, ActiSham offers better participants’ blinding by inducing very similar scalp sensations to those of real Multifocal tDCS both in terms of intensity and localization, while not affecting corticospinal excitability.

Summary Background For safety assessment in clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with AEs in the placebo group. Little is known about the nature of the AEs associated with clinical trials of SARS-CoV-2 vaccines and the extent to which these can be traced to nocebo effects, where negative treatment-related expectations favor their occurrence. Methods In our systematic review, we compared the rates of solicited AEs in the active and placebo groups of SARS-CoV-2 vaccines approved by the Western pharmaceutical regulatory agencies. We implemented a search strategy to identify trial-III studies of SARS-CoV-2 vaccines through the PubMed database. We adopted the PRISMA Statement to perform the study selection and the data collection and identified three trial: two mRNA-based (38403 participants) and one adenovirus type (6736 participants). Findings Relative risks showed that the occurrence of AEs reported in the vaccine groups was higher compared with the placebo groups. The most frequently AEs in both groups were fatigue, headache, local pain, as injection site reactions, and myalgia. In particular, for first doses in placebo recipients, fatigue was reported in 29% and 27% in BNT162b2 and mRNA-1273 groups, respectively, and in 21% of Ad26.COV2.S participants. Headache was reported in 27% in both mRNA groups and in 24% of Ad26.COV2.S recipients. Myalgia was reported in 10% and 14% in mRNA groups (BNT162b2 and mRNA-1273, respectively) and in 13% of Ad26.COV2.S participants. Local pain was reported in 12% and 17% in mRNA groups (BNT162b2 and mRNA-1273, respectively), and in 17% of Ad26.COV2.S recipients. These AEs are more common in the younger population and in the first dose of placebo recipients of the mRNA vaccines. Interpretation Our results are in agreement with the expectancy theory of nocebo effects and suggest that the AEs associated with COVID-19 vaccines may be related to the nocebo effect. Funding Fondazione CRT - Cassa di Risparmio di Torino, IT (grant number 66346, "GAIA-MENTE" 2019).

Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine-resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time-consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine-resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment.

As part of studies that employ health electronic records databases, this paper advocates the employment of graph theory for investigating drug-switching behaviors. Unlike the shared approach in this field (comparing groups that have switched with control groups), network theory can provide information about actual switching behavior patterns. After a brief and simple introduction to fundamental concepts of network theory, here we present (i) a Python script to obtain an adjacency matrix from a records database and (ii) an illustrative example of the application of network theory basic concepts to investigate drug-switching behaviors. Further potentialities of network theory (weighted matrices and the use of clustering algorithms), along with the generalization of these methods to other kinds of switching behaviors beyond drug switching, are discussed.

Aims Experimental studies show that some antiepileptic drugs (AEDs) may modify natural immune defences, thus influencing the risk of developing infectious diseases. The aim of this meta-analysis was to explore whether AEDs as a class of drugs or singularly may increase risk of infectious diseases. Methods A meta-analysis of all randomized, double-blind, placebo-controlled trials (RCTs) investigating any AED in any condition was performed. All terms that could be coded in the System Organ Classes (SOCs) of infections and infestations using the Medical Dictionary for Regulatory Activities were recorded. Additional subanalyses were performed also pooling together AEDs sharing similar mechanisms of action. Results Two hundreds and sixty-nine double-blind, placebo-controlled studies were identified and, among them, 127 RCTs with 16 AEDs (brivaracetam, gabapentin, lacosamide, levetiracetam, lamotrigine, oxcarbazepine, perampanel, pregabalin, phenytoin, remacemide, retigabine, rufinamide, tiagabine, topiramate, valproate, zonisamide) reported at least one of 19 symptoms or diseases that could be included in the Medical Dictionary for Regulatory Activities SOC term infections and infestations. These terms were singularly recorded and then pooled together in the SOC term infection and infestation. Topiramate was significantly associated with an increased risk of infection (risk difference = 0.04; 95% confidence interval = 0.01/0.06), while oxcarbazepine was significantly associated with a lower risk (–0.005; –0.09/–0.01). Risk difference of all studies with all AEDs showed a slight, but significantly increased risk of infection (0.01; 0.00/0.002). Levetiracetam and brivaracetam RCTs, when pooled together, were associated with a significantly increased risk of infection (0.03; 0.01/0.05). Conclusions Some AEDs are associated with a mild increased risk of infection.

Background: Antipsychotic clinical trials use to present adverse events (AEs) for the drug under evaluation to treat schizophrenia. Interestingly, patients who receive the placebo during antipsychotic trials often report several AEs, but little is known about the essence of these negative effects in patients with schizophrenia spectrum disorders (SCD). In the present meta-analysis, we evaluated the relationship between the level of psychiatric symptomatology expressed as Positive and Negative Syndrome Scale (PANSS) scores and the rates of AEs reported in the placebo arms of double-blind clinical trials, for commonly prescribed atypical antipsychotic medications. Methods: We selected 58 clinical trials describing AEs in SCD placebo groups, which compared atypical antipsychotic medications with placebo. A total of 6,301 placebo-treated patients were considered. AE profiles of the class were clusterized using MedDRA classification and analysed using a meta-regression approach. Results: In the placebo arms the proportions of patients with any AE was 66.3% (95% CI: 62.7–69.8%). The proportion of withdrawal of patients treated with placebo because of AEs was 7.2% (95% CI: 5.9–8.4%). Interestingly, the AEs in the placebo arms corresponded to those of the antipsychotic-atypical-medication-class against which the placebo was compared. Namely, using meta-regression analysis we found an association between the level of psychiatric symptomatology measured with PANSS scores and higher AEs reported as nervous system (p = 0.020) and gastrintestinal disorders (p = 0.004). Moreover, the level of a higher psychiatric symptomatology expressed with PANSS scores was also related with higher AEs associated with psychiatric symptoms (p = 0.017). Conclusion: These findings emphasise that the AEs in placebo arms of clinical trials of antipsychotic medications were substantial. Importantly, a higher level of psychiatric symptomatology makes SCD patients more prone to express AEs, thus contributing to possible drop-outs and to a lower adherence to treatments. These results are consistent with the expectation theory of placebo and nocebo effects.

Neurological disorders constitute the etiological factors of symptomatic epilepsies. However, in recent times, there are evidences that there is a mutual strong interaction between epilepsy and other diseases of the central nervous system and that in some cases these may be caused by a hidden etiologic factor that has been called “systemic dysfunction.” Furthermore, in all cases epilepsy and comorbid neurologic diseases influence each other through several mechanisms, including drug treatments. The consequence of this approach is that treatment strategy should consider, at the same time, all diseases that affect brain function. Epilepsy and cerebrovascular diseases are frequently associated, and the interaction between these diseases affect prognosis. Choice of treatments is of strategic importance. For example, there are antiepileptic drugs that may worsen vascular disease and negatively interact with drugs used for vascular disorder. This applies also to comorbidity with infectious diseases, brain tumors, and several neurodegenerative diseases.

The ability to flexibly regulate our behavior is a fundamental feature of human cognition and requires efficient functioning of cognitive control. During movement preparation, proactive inhibitory control plays a crucial role in regulating the excitatory activity carried out by alertness. The balance between alertness and proactive inhibition could be altered in people with motor impulsivity trait, determining the typical failure in the inhibition of prepotent motor responses. To test this hypothesis, 36 young adults were administered the Barratt Impulsiveness Scale to assess motor impulsivity trait and underwent fMRI acquisition during the execution of an event-related Go/Nogo task. To investigate motor preparation processes, we analyzed the "readiness" period, in which subjects were waiting and preparing for the upcoming stimulus (Go or Nogo). We found a positive significant correlation between motor impulsivity scores and the activation of left sensorimotor cortices. This result indicates that motor impulsivity trait might be associated with a disinhibition of the motor system, characterized by a diminished reactivity threshold and a reduced control over covert urges. Furthermore, we observed a positive significant correlation between motor impulsivity scores and the activation in left inferior and superior parietal lobule, which might be related to a more pronounced proactive control, probably reflecting a compensatory mechanism implemented by participants with a higher degree of motor impulsivity trait to reach a correct inhibition. Current findings provide a rationale for further studies aiming to better understand proactive control functioning in healthy impulsive subjects and under clinical conditions.

The present investigation explores the role of bottom-up and top-down factors in the recognition of emotional facial expressions during binocular rivalry. We manipulated spatial frequencies (SF) and emotive features and asked subjects to indicate whether the emotional or the neutral expression was dominant during binocular rivalry. Controlling the bottom-up saliency with a computational model, physically comparable happy and fearful faces were presented dichoptically with neutral faces. The results showed the dominance of emotional faces over neutral ones. In particular, happy faces were reported more frequently as the first dominant percept even in the presence of coarse information (at a low SF level: 2&ndash, 6 cycle/degree). Following current theories of emotion processing, the results provide further support for the influence of positive compared to negative meaning on binocular rivalry and, for the first time, showed that individuals perceive the affective quality of happiness even in the absence of details in the visual display. Furthermore, our findings represent an advance in knowledge regarding the association between the high- and low-level mechanisms behind binocular rivalry.

Deficient voluntary control of behaviour and impulsivity are key aspects of impulse control disorders. The objective of the present study was to evaluate the relationship between behavioural measures of impulsivity and the awareness of voluntary action. Seventy-four healthy volunteers completed the Barratt Impulsiveness Scale (BIS), a questionnaire used to measure impulsive personality traits, and a go/no-go task. Moreover, all participants performed a behavioural task based on the Libet's clock paradigm in which they were requested to report the time of a self-initiated movement (M-judgement) or the time they first feel their intention to move (W-judgement). A positive relationship between the time in which subjects reported the intention to move (W-judgement) and impulsivity measures emerged. Namely, the higher was the score in the attentional and motor impulsivity subscales of the BIS and the number of inhibitory failure responses in the go/no-go task, the lower was the difference between the W-judgement and the actual movement (i.e. the awareness of intention to move was closer to the voluntary movement execution). In contrast, no relationship emerged with M-judgement. The present findings suggest that impulsivity is related to a delayed awareness of voluntary action. We hypothesize that in impulse control disorders, the short interval between conscious intention and actual movement may interfere with processes underlying the conscious 'veto' of the impending action.

The aim of this study was to assess the nocebo effect in all randomised controlled trials (RCTs) exploring the effect of antiepileptic drugs (AEDs) in the clinical conditions in which these compounds have been studied with the exception of epilepsy. We searched for all double-blind, placebo-controlled trials performed in adult patients, testing AEDs in any clinical condition except epilepsy. The following data were extracted from the placebo arms: the number of randomized patients, the number of patients withdrawing because of adverse effects (AEs), and the number of patients with 11 predefined AEs (dizziness, ataxia/coordination abnormal, diplopia, somnolence, fatigue, headache, memory impairment, tremor, abnormal thinking, anxiety and depression). Outcome measures were the percentages of patients whithdrawing due to AEs and reporting the selected AEs. RCTs included in the analysis were grouped in six main categories of clinical conditions (pain, movement disorders, psychiatric disorders, substance abuse, obesity and binge eating disorders, and miscellanea). Proportions of patients with 95 % confidence intervals (CIs) have been calculated for all reported outcome measures. Thirteen AEDs were studied and the total number of selected RCTs was 157. Significant percentages of placebo-treated patients withdrawing due to AEs and with specific AEs were observed in several cases. Significant differences emerged across different conditions. Comparisons with results of a previous meta-analysis on all RCTs in patients with drug-resistant epilepsies showed that ataxia, diplopia and fatigue were significantly more frequent, and patients withdrawing were significantly less frequent, in placebo-treated epileptic patients. Significant differences have been identified in the AEDs-induced nocebo effect across different conditions. Placebo-treated epilepsy patients have significantly more frequent neurological AEs.

In this study, we conducted two experiments to evaluate the effect of different types of odors on a time reproduction task, comparing performances of males to those of females. In the first experiment, subjects had to estimate short (510, 600, 690 ms) and long (1700, 2000, 2300 ms) interval durations under three odor conditions: positive, negative and neutral. A gender specific effect of olfactory stimulation on time estimation was found only for short durations. Namely, females were less accurate (overestimated) in reproducing short time intervals during the unpleasant odor presentation. This effect was confirmed and strengthened in the second experiment in which the intensity of the negative odor was enhanced. The present findings suggest that the neural network underlying time estimation is more “sensitive” to context manipulations in females than in men. Practical Applications The first important point is that there might be relevant gender differences in the processing of time (time estimation) that are mediated by olfactory stimulation. This new evidence might have important implications and applications in health issues and especially in workplace safety, for example in jobs or contexts in which fast processing and rapid decisions or choices are required. Therefore, the knowledge that females are more influenced by unpleasant odors than males during time estimation should be seriously considered in situations in which time plays a crucial role such as during rapid decision-making, where automatic processes should be efficiently activated. Overall, the higher sensitivity to specific olfactory stimulation observed in women probably reflects individual differences in a complex process such as time processing.

Second and third generation AEDs have been directly compared to controlled-release carbamazepine (CBZ-CR) as initial monotherapy for new-onset focal epilepsy. Conversely, no head-to-head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta-analysis (NMA). Randomized, double-blinded, parallel group, monotherapy studies comparing any AED to CBZ-CR in adults with newly diagnosed untreated epilepsy with focal-onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12 months, the occurrence of treatment-emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ-CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR-CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6- and 12-month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ-CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ-CR (OR 0.659, 95% CrI 0.428-0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ-CR.

The notion of default mode network (DMN) and the dual process theory of thought, topics within different cognitive neuroscience and psychology subfields, have attracted considerable attention and been extensively studied in the past decade. The former originated from experimental evidence on the brain function obtained when an individual is not involved in a specific task, and recent research suggests that the DMN plays a role in mental and neurological disorders (Buckner et al., 2008). A distinction is made according to the psychology of thinking in the dual process theory of thought between fast, effortless associative processes and slow, deliberative ones (Kahneman, 2011). This theory has been exploited both theoretically, to better understand human thought, and in many applications of behavior modification (Thaler and Sunstein, 2008). This paper proposes that an amalgamation of the aspects of these two topics could be of mutual benefit to scientists within the respective fields. The discovery of the DMN has stimulated several hypotheses regarding the neural basis of the self and the theory of the mind. However, with few exceptions, these hypotheses lack reference to current research on thought processes like reasoning and decision-making. A role of the DMN in the organization and expression of preplanned, reflexive behaviors characteristics of fast thinking has been mentioned by Raichle (2015). Moreover, a link between fast and slow processes and the activity of neural circuits including the DMN, has been proposed in the framework of the Predictive And Reactive Control Systems (PARCS) theory (Tops et al., 2014). More recently, the contribution of the DMN to automated processing has been also suggested (Vatansever et al., 2017). In contrast, the dual process theory of thought is the most shared explanation of how thoughts arise but does not adequately address the neural basis of thought, although an attempt has been made to determine the relationship between ego depletion and biological parameters (Elkins-Brown et al., 2016). Thus, in our opinion the DMN may provide a neural foundation for the associative, fast, and effortless form of thinking elucidated by the dual process theory.

Background The Oxford Cognitive Screen (OCS) was recently developed with the aim of describing the cognitive deficits after stroke. The scale consists of 10 tasks encompassing five cognitive domains: attention and executive function, language, memory, number processing, and praxis. OCS was devised to be inclusive and un-confounded by aphasia and neglect. As such, it may have a greater potential to be informative on stroke cognitive deficits of widely used instruments, such as the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment, which were originally devised for demented patients. Objective The present study compared the OCS with the MMSE with regards to their ability to detect cognitive impairments post-stroke. We further aimed to examine performance on the OCS as a function of subtypes of cerebral infarction and clinical severity. Methods 325 first stroke patients were consecutively enrolled in the study over a 9-month period. The OCS and MMSE, as well as the Bamford classification and NIHSS, were given according to standard procedures. Results About a third of patients (35.3%) had a performance lower than the cutoff ( Conclusion Overall, the results showed a much higher incidence of cognitive impairment with the OCS than with the MMSE and demonstrated no false negatives for OCS vs MMSE. It is concluded that OCS is a sensitive screen tool for cognitive deficits after stroke. In particular, the OCS detects high incidences of stroke-specific cognitive impairments, not detected by the MMSE, demonstrating the importance of cognitive profiling.

The positivity effect in the elderly consists of an attentional preference for positive information as well as avoidance of negative information. Extant theories predict either that the positivity effect depends on controlled attentional processes (socio-emotional selectivity theory), or on an automatic gating selection mechanism (dynamic integration theory). This study examined the role of automatic and controlled attention in the positivity effect. Two dot-probe tasks (with the duration of the stimuli lasting 100 ms and 500 ms, respectively) were employed to compare the attentional bias of 35 elderly people to that of 35 young adults. The stimuli used were expressive faces displaying neutral, disgusted, fearful, and happy expressions. In comparison to young people, the elderly allocated more attention to happy faces at 100 ms and they tended to avoid fearful faces at 500 ms. The findings are not predicted by either theory taken alone, but support the hypothesis that the positivity effect in the elderly is driven by two different processes: an automatic attention bias toward positive stimuli, and a controlled mechanism that diverts attention away from negative stimuli.

We assessed the effects of a non-invasive neuromodulatory intervention with repetitive transcranial magnetic stimulation (rTMS) of the motor cortex in patients with vegetative state (VS) by a randomised, sham-controlled study with a cross-over design. Eleven patients classified as being in VS (9 post-anoxic, 2 post-traumatic, time elapsed from the injury 9-85 months) were included in the study. Real or sham 20 Hz rTMS were applied to the left primary motor cortex (M1) for 5 consecutive days. Primary outcome measures were changes in the JFK Coma Recovery Scale-Revised (CRS-R) scale total score and Clinical Global Impression Improvement (CGI-I) scale. Additional measures were EEG changes and impression of the patients' relatives using the CGI-I scale. Evaluations were blindly performed at baseline, after the first day of treatment, immediately after the end of the 5-days treatment, 1 week and 1 month later. Slight changes observed in the CRS-R and CGI-I scores did not significantly differ between real or sham stimulation conditions. EEG was not significantly changed on average, although spots of brain reactivity were occasionally found underneath the stimulation point. Findings did not provide evidence of therapeutic effect of 20 Hz rTMS of the M1 in chronic VS, at least with conventional coils and current safety parameters. Therefore, they might be useful to better allocate human and financial resources in future trials.

Objective The cortical silent period (CSP) following transcranial magnetic stimulation reflects GABAB-mediated inhibition in the primary motor cortex (M1) and could contribute to understand the pathophysiological substrates of epileptic conditions. Increased CSP duration has been reported in idiopathic generalized epilepsy (IGE) and in partial epilepsy (PE) involving the M1, although other studies yielded discordant findings. We used meta-analysis to systematically assess the consistency of CSP changes in untreated patients with epilepsies. Methods Databases were searched for controlled studies evaluating the CSP in drug-naive or drug-free patients with IGE or PE. For each study, the mean difference with 95% confidence intervals (CIs) between CSP duration obtained in patients and controls was calculated. The effect of motor threshold (MT) on the CSP duration has also been explored by meta-analysis and meta-regression. Results Fourteen studies (267 patients and 234 controls) were included. A significant mean difference (14.16 ms, 95% CI, 1.20, 27.11 ms) was found, with longer CSP in patients than in controls. The mean difference was still greater (18.05 ms) if only the 202 IGE patients were analyzed. No MT difference emerged between patients and controls. Meta-regression showed no relationship between MT and CSP duration. Conclusion Meta-analysis confirms CSP modifications in epilepsies, with enhancement of this cortical inhibitory measure at least in most IGE patients. This provides rationale for further investigations aiming to verify the hypotheses that increased CSP reflects compensatory neural phenomena counteracting transition from the interictal to ictal state and that CSP variability reflects the pathophysiological heterogeneity of epileptic syndromes.

In ten healthy subjects and in ten patients suffering from Multiple Sclerosis (MS), we investigated the cortical functional changes induced by a standard fatiguing repetitive tapping task. The Cortical Silent Period (CSP), an intracortical, mainlyGABAB-mediated inhibitory phenomenon, was recorded by two different hand muscles, one acting as prime mover of the fatiguing index-thumb tapping task (First Dorsal Interosseous, FDI) and the other one not involved in the task but sharing largely overlapping central, spinal, and peripheral innervation (Abductor Digiti Minimi, ADM). At baseline, the CSP was shorter in patients than in controls. As fatigue developed, CSP changes involved both the “fatigued” FDI and the “unfatigued” ADM muscles, suggesting a cortical spread of central fatigue mechanisms. Chronic therapy with amantadine annulled differences in CSP duration between controls and patients, possibly through restoration of more physiological levels of intracortical inhibition in the motor cortex. These inhibitory changes correlated with the improvement of fatigue scales. The CSP may represent a suitable marker of neurophysiological mechanisms accounting for central fatigue generation either in controls or in MS patients, involving corticospinal neural pools supplying not only the fatigued muscle but also adjacent muscles sharing an overlapping cortical representation.

Electrophysiological and neuroimaging studies suggest that our actions are initiated by unconscious mental processes long before awareness of intention to act. The time window between the awareness of the intention to move and the movement onset, which normally permits to exert a conscious “veto” on the impending action, is modulated by individual differences in trait impulsivity. In particular, trait impulsive people show a delayed awareness of the intention to act, probably exceeding the “point of no return”, after which the action can no longer be inhibited. In order to investigate if individual differences in the “veto” interval might be explained by differences in the readiness potential (RP) dynamics, nineteen healthy participants underwent an impulsivity trait assessment using the Barratt Impulsiveness Scale (BIS-11) and performed a task based on Libet’s clock paradigm, during EEG recordings of pre-movement neural activity. We observed a positive relationship between impulsive personality trait and motor system excitability during the preparation of self-initiated movements. In particular, the RP showed an earlier negative rising phase and a greater amplitude, with the increasing of BIS-11 scores. Based on present results, we conclude hypothesizing that trait impulsivity might be characterized by less effective preparatory inhibition mechanisms, which have a fundamental role in the control of behavior.

ObjectiveThe objective of this study was to perform a comparative assessment of tolerability of all licensed new antiepileptic drugs (AEDs) through a network meta-analysis (NMA) including all placebo-controlled double-blind clinical trials (RCTs) in all conditions in which these drugs have been tested.MethodsNMA with a frequentist approach was used to compare proportions of patients withdrawing because of adverse events (AEs). Analyses were conducted for all therapeutic doses pooled and specifically for high therapeutic doses. Patients treated with non-therapeutic doses of each drug were excluded.ResultsA total of 195 RCTs were included in the current analysis, comprising a total of 28,013 patients treated with AEDs and 17,908 patients treated with placebo. RCTs included in the analysis were 8 for brivaracetam; 5 for eslicarbazepine; 22 for gabapentin; 7 for lacosamide; 14 for levetiracetam; 14 for lamotrigine; 6 for oxcarbazepine; 9 for perampanel; 50 for pregabalin; 5 for tiagabine; 36 for topiramate; 7 for zonisamide; 4 for gabapentin-extended formulation (ER); 2 each for levetiracetam-ER, lamotrigine-ER, and topiramate-ER; and 1 each for oxcarbazepine-ER and pregabalin-ER. Brivaracetam, gabapentin, gabapentin-ER, and levetiracetam had a significantly lower withdrawal rate compared to several other AEDs, while eslicarbazepine, lacosamide, oxcarbazepine, and topiramate had a higher withdrawal rate. Perampanel, lamotrigine, pregabalin, tiagabine, and zonisamide showed an intermediate pattern of tolerability. Additional analysis has been conducted through selection of highly recommended doses for each drug. This analysis has roughly confirmed results of head to head comparisons of the all-dose analysis, with some exceptions. A further analysis has been conducted after exclusion of RCTs in which patients were allocated to the therapeutic dose of the experimental drug without titration, and it failed to show clinically important differences.SignificanceRelevant differences in short-term tolerability of AEDs have been observed between AEDs. Brivaracetam, gabapentin, and levetiracetam show the best tolerability profile while other AEDs are at higher risk for intolerable adverse effects.

The identification of signs of awareness in patients with prolonged disorders of consciousness (DoC) after severe brain injury is a challenging task for clinicians. Differentiating on behavioural examination the vegetative state (VS) from the minimally conscious state (MCS) can lead to a high misdiagnosis rate. Advanced neuroimaging and neurophysiological techniques can supplement clinical evaluation by providing physiological evidence of brain activity. However, an open issue remains whether these empirical results are directly or indirectly associated with covert consciousness and limitations emerge for their diagnostic application at the single-patient level. On the therapeutic side, the efficacy of both non-invasive and invasive brain stimulation/modulation trials is matter of debate. The present review provides an updated analysis of the diagnostic and prognostic impact that the different neurophysiological techniques of stimulation [including short-latency evoked potentials, long-latency event related potentials (ERPs), transcranial magnetic stimulation (TMS), TMS-EEG co-registration] offer in prolonged DoC. The results of the therapeutic stimulation techniques are also evaluated. It is concluded that TMS-EEG emerges as the most promising tool for differentiating VS from MCS whereas ERPs allow neurophysiologists to probe covert cognitive capacities of each patient. Significant behavioural improvements in prolonged DoC with brain stimulation techniques are still anecdotical and further treatment options are awaited.

Background The automatic analysis of facial expressions is an evolving field that finds several clinical applications. One of these applications is the study of facial bradykinesia in Parkinson’s disease (PD), which is a major motor sign of this neurodegenerative illness. Facial bradykinesia consists in the reduction/loss of facial movements and emotional facial expressions called hypomimia. New method In this work we propose an automatic method for studying facial expressions in PD patients relying on video-based Methods 17 Parkinsonian patients and 17 healthy control subjects were asked to show basic facial expressions, upon request of the clinician and after the imitation of a visual cue on a screen. Through an existing face tracker, the Euclidean distance of the facial model from a neutral baseline was computed in order to quantify the changes in facial expressivity during the tasks. Moreover, an automatic facial expressions recognition algorithm was trained in order to study how PD expressions differed from the standard expressions. Results Results show that control subjects reported on average higher distances than PD patients along the tasks. Comparison with existing methods This confirms that control subjects show larger movements during both posed and imitated facial expressions. Moreover, our results demonstrate that anger and disgust are the two most impaired expressions in PD patients. Conclusions Contactless video-based systems can be important techniques for analyzing facial expressions also in rehabilitation, in particular speech therapy, where patients could get a definite advantage from a real-time feedback about the proper facial expressions/movements to perform.

Purpose Analysis of overall tolerability and neurological adverse effects (AEs) of eslicarbazepine acetate (ESL), lacosamide (LCM) and oxcarbazepine (OXC) from double-blind, placebo-controlled trials. Indirect comparisons of patients withdrawing because of AEs, and the incidence of some vestibulocerebellar AEs between these three antiepileptic dugs (AEDs). Methods We searched MEDLINE for all randomized, double-blind, placebo-controlled trials investigating therapeutic effects of fixed oral doses of ESL, LCM and OXC in patients with drug resistant epilepsy. Withdrawal rate due to AEs, percentages of patients with serious AEs, and the proportion of patients experiencing any neurological AE, nausea and vomiting were assessed for their association with the experimental drug. Analyses were performed between recommended daily doses of each AED according to the approved summary of product characteristics (SPC). Risk differences were used to evaluate the association of any AE [99% confidence intervals (CIs)] or study withdrawals because of AEs (95% CIs) with the experimental drug. Indirect comparisons between withdrawal rate and AEs dizziness, coordination abnormal/ataxia and diplopia were estimated according to network meta-analysis (Net-MA). Results Eight randomized, placebo-controlled, double-blind trials (4 with ESL, 3 with LCM, and 1 with OXC) were included in our analysis. At high doses (OXC 1200mg, ESL 1200mg and LCM 400mg) there was an increased risk of AE-related study withdrawals compared to placebo for all drugs. Several AEs were associated with the experimental drug. Both number and frequency of AEs were dose-related. At high recommended doses, patients treated with OXC withdrew from the experimental treatment significantly more frequently than patients treated with ESL and LCM. Furthermore, the AEs coordination abnormal/ataxia and diplopia were significantly more frequently observed in patients treated with OXC compared to patients treated with LCM and ESL. Conclusions The overall tolerability of AEDs and the incidence of several neurological AEs were clearly dose-dependent. Indirect comparisons between these AEDs, taking into account dose-effect, showed that OXC may be associated with more frequent neurological AEs than LCM and ESL.

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the postsynaptic membrane are involved in fast excitatory signaling in the brain and their activation may lead to the firing of action potentials. Talampanel and perampanel were the first noncompetitive AMPA receptor antagonists to be tested as add-on drugs in patients with refractory partial seizures, and were found to be effective in improving seizure control. Due to an unfavorable kinetic and tolerability profile, talampanel clinical development in the field of epilepsy was discontinued early while perampanel has been recently approved in Europe and the USA as adjunctive therapy for adults with partial seizures with or without secondary generalization. The recommended perampanel starting dose is 2 mg/day once daily, which can be increased up to the recommended maintenance dose of 4-8 mg/day. Increments should be of 2 mg/day and based on clinical response and tolerability. Titration should be performed at 1-week intervals or at lower speed and a 12-mg daily dose should be considered after careful evaluation. To date, no serious and/or idiosyncratic adverse effects have been associated with this agent. Most frequently reported adverse effects are dizziness, ataxia, aggression, irritability, vertigo, somnolence, fatigue, headache and gait disturbance. Weight increase is the only non-neurological adverse effects associated with perampanel.

Synchronization of body movements to an external beat is a universal human ability, which has also been recently documented in nonhuman species. The neural substrates of this rhythmic motor entrainment are still under investigation. Correlational neuroimaging data suggest an involvement of the dorsal premotor cortex (dPMC) and the supplementary motor area (SMA). In 14 healthy volunteers, we more specifically investigated the neural network underlying this phenomenon using a causal approach by an established 1-Hz repetitive transcranial magnetic stimulation (rTMS) protocol, which produces a focal suppression of cortical excitability outlasting the stimulation period. Synchronization accuracy between rhythmic cues and right index finger tapping, as measured by the mean time lag (asynchrony) between motor and auditory events, was significantly affected when the right dPMC function was transiently perturbed by "off-line" focal rTMS, whereas the reproduction of the rhythmic sequence per se (inter-tap-interval) was spared. This approach affected metrical rhythms of different complexity, but not non-metrical or isochronous sequences. Conversely, no change in auditory-motor synchronization was observed with rTMS of the SMA, of the left dPMC or over a control site (midline occipital area). Our data strongly support the view that the right dPMC is crucial for rhythmic auditory-motor synchronization in humans.

Converging results have shown that adults benefit from congruent multisensory stimulation in the identification of complex stimuli, whereas the developmental trajectory of the ability to integrate multisensory inputs in children is less well understood. In this study we explored the effects of audiovisual semantic congruency on identification of visually presented stimuli belonging to different categories, using a cross-modal approach. Four groups of children ranging in age from 6 to 13 years and adults were administered an object identification task of visually presented pictures belonging to living and nonliving entities. Stimuli were presented in visual, congruent audiovisual, incongruent audiovisual, and noise conditions. Results showed that children under 12 years of age did not benefit from multisensory presentation in speeding up the identification. In children the incoherent audiovisual condition had an interfering effect, especially for the identification of living things. These data suggest that the facilitating effect of the audiovisual interaction into semantic factors undergoes developmental changes and the consolidation of adult-like processing of multisensory stimuli begins in late childhood. (PsycINFO Database Record

Summary Objectives A large percentage of patients with Parkinson's disease have hypokinetic dysarthria, exhibiting reduced peak velocities of jaw and lips during speech. This limitation implies a reduction of speech intelligibility for such patients. This work aims at testing a cost-effective markerless approach for assessing kinematic parameters of hypokinetic dysarthria. Study Design Kinematic parameters of the lips are calculated during a syllable repetition task from 14 Parkinsonian patients and 14 age-matched control subjects. Methods Combining color and depth frames provided by a depth sensor (Microsoft Kinect), we computed the three-dimensional coordinates of main facial points. The peak velocities and accelerations of the lower lip during a syllable repetition task are considered to compare the two groups. Results Results show that Parkinsonian patients exhibit reduced peak velocities of the lower lip, both during the opening and the closing phase of the mouth. In addition, peak values of acceleration are reduced in Parkinsonian patients, although with significant differences only in the opening phase with respect to healthy control subjects. Conclusions The novel contribution of this work is the implementation of an entirely markerless technique capable to detect signs of hypokinetic dysarthria for the analysis of articulatory movements during speech. Although a large number of Parkinsonian patients have hypokinetic dysarthria, only a small percentage of them undergoes speech therapy to increase their articulatory movements. The system proposed here could be easily implemented in a home environment, thus, increasing the percentage of patients who can perform speech rehabilitation at home.

Summary Purpose: Defining the tolerability and safety profile of recently marketed antiepileptic drugs, such as lacosamide (LCM), is a prerequisite for their optimal utilization in clinical practice. We aimed to identify any adverse event (AE) associated with LCM treatment by conducting a systematic review and meta-analysis of all available randomized controlled trials (RCTs). We also evaluated the association of serious AEs with LCM, the proportion of study withdrawals due to intolerable AEs at different LCM doses, and whether the tolerability profile of LCM differs according to the disorder in which it was investigated. Methods: We searched MEDLINE and Cochrane CENTRAL to May 2011 for LCM RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo-controlled, double-blind RCTs and investigated the therapeutic effects of oral LCM in adults with any condition. AEs were assessed for their association with LCM after identification/exclusion of synonyms, rare AEs, and non-assessable AEs. We used risk differences to evaluate the association of any (99% confidence intervals [CIs]) or serious AEs (95% CIs) with LCM and to investigate dose–response relationships of identified AEs. Key Findings: Ten RCTs (three in pharmacoresistant epilepsy, four in neuropathic pain, one in migraine, one in fibromyalgia, and one in knee osteoarthritis) were included in our study. Their duration varied from 12–18 weeks. The total number of patients included was 3,148. No serious AE was significantly associated with LCM treatment. Of 21 identified AEs, 11 (52%) were found to be significantly associated with LCM. The number of AEs significantly associated with LCM increased with increasing dose: one at 200 mg/day (dizziness); six at 400 mg/day (dizziness, vertigo, abnormal coordination, abnormal vision, nausea, and vomiting); nine at 600 mg/day (dizziness, vertigo, ataxia, balance disorder, diplopia, fatigue, nausea, vomiting, and tremor). The proportion of AE-related study withdrawals also significantly increased with increasing dose. LCM AEs tended to occur more frequently in patients with drug-resistant epilepsy compared with patients with other disorders. Significance: A range of AEs suggestive of vestibulocerebellar dysfunction is significantly associated with LCM treatment and their incidence increases with increasing doses.