Fabio Giovannelli

Frequency-Dependent Enhancement of Fluid Intelligence Induced by Transcranial Oscillatory Potentials

Everyday problem solving requires the ability to go beyond experience by efficiently encoding and manipulating new information, i.e., fluid intelligence (Gf) [1]. Performance in tasks involving Gf, such as logical and abstract reasoning, has been shown to rely on distributed neural networks, with a crucial role played by prefrontal regions [2]. Synchronization of neuronal activity in the gamma band is a ubiquitous phenomenon within the brain; however, no evidence of its causal involvement in cognition exists to date [3]. Here, we show an enhancement of Gf ability in a cognitive task induced by exogenous rhythmic stimulation within the gamma band. Imperceptible alternating current [4] delivered through the scalp over the left middle frontal gyrus resulted in a frequency-specific shortening of the time required to find the correct solution in a visuospatial abstract reasoning task classically employed to measure Gf abilities (i.e., Ravens matrices) [5]. Crucially, gamma-band stimulation (γ-tACS) selectively enhanced performance only on more complex trials involving conditional/logical reasoning. The present finding supports a direct involvement of gamma oscillatory activity in the mechanisms underlying higher-order human cognition.

Modulation of interhemispheric inhibition by volitional motor activity: an ipsilateral silent period study

Brief interruption of voluntary EMG in a hand muscle by focal transcranial magnetic stimulation (TMS) of the ipsilateral primary motor cortex (M1), the so‐called ipsilateral silent period (ISP), is a measure of interhemispheric motor inhibition. However, little is known about how volitional motor activity would modulate the ISP. Here we tested in 30 healthy adults to what extent and under what conditions voluntary activation of the stimulated right M1 by moving the left hand strengthens interhemispheric inhibition as indexed by an enhancement of the ISP area in the maximally contracting right first dorsal interosseous (FDI). Left index finger abduction, already at low levels of contraction, significantly enhanced the ISP compared to left hand at rest. Even imagination of left index finger movement enhanced the ISP compared to rest or mental calculation. This enhancement occurred in the absence of motor‐evoked potential amplitude modulation in the left FDI, thus excluding a non‐specific contribution from an increase in right M1 corticospinal excitability. Contraction of the left extensor indicis, but not contraction of more proximal left upper limb or left or right lower limb muscles also enhanced the ISP. A reaction time experiment showed that the ISP enhancement developed at a late stage of movement preparation just before or at movement onset. Interhemispheric inhibition of the motor‐evoked potential as tested by a bifocal paired‐pulse TMS protocol and thought to be mediated via a neuronal circuit different to the ISP was not enhanced when tested under identical motor task conditions. Finally, ISP enhancement by contraction of the left FDI correlated inversely with EMG mirror activity in the right FDI during phasic abductions of the left index finger. Our findings strongly suggest that voluntary M1 activation by real or imagined movement of the contralateral hand increases interhemispheric motor inhibition of the opposite M1. This phenomenon shows substantial topographical, temporal and neuronal circuit specificity, and has functional significance as it probably plays a pivotal role in suppressing mirror activity.

Vegetative versus Minimally Conscious States: A Study Using TMS-EEG, Sensory and Event-Related Potentials

Differential diagnoses between vegetative and minimally conscious states (VS and MCS, respectively) are frequently incorrect. Hence, further research is necessary to improve the diagnostic accuracy at the bedside. The main neuropathological feature of VS is the diffuse damage of cortical and subcortical connections. Starting with this premise, we used electroencephalography (EEG) recordings to evaluate the cortical reactivity and effective connectivity during transcranial magnetic stimulation (TMS) in chronic VS or MCS patients. Moreover, the TMS-EEG data were compared with the results from standard somatosensory-evoked potentials (SEPs) and event-related potentials (ERPs). Thirteen patients with chronic consciousness disorders were examined at their bedsides. A group of healthy volunteers served as the control group. The amplitudes (reactivity) and scalp distributions (connectivity) of the cortical potentials evoked by TMS (TEPs) of the primary motor cortex were measured. Short-latency median nerve SEPs and auditory ERPs were also recorded. Reproducible TEPs were present in all control subjects in both the ipsilateral and the contralateral hemispheres relative to the site of the TMS. The amplitudes of the ipsilateral and contralateral TEPs were reduced in four of the five MCS patients, and the TEPs were bilaterally absent in one MCS patient. Among the VS patients, five did not manifest ipsilateral or contralateral TEPs, and three of the patients exhibited only ipsilateral TEPs with reduced amplitudes. The SEPs were altered in five VS and two MCS patients but did not correlate with the clinical diagnosis. The ERPs were impaired in all patients and did not correlate with the clinical diagnosis. These TEP results suggest that cortical reactivity and connectivity are severely impaired in all VS patients, whereas in most MCS patients, the TEPs are preserved but with abnormal features. Therefore, TEPs may add valuable information to the current clinical and neurophysiological assessment of chronic consciousness disorders.

A novel DCC mutation and genetic heterogeneity in congenital mirror movements

Objective: DCC is the receptor for netrin, a protein that guides axon migration of developing neurons across the bodys midline. Mutations in the DCC gene were recently identified in 2 families with congenital mirror movements (MM). The objective was to study clinical and genetic characteristics of 3 European families with MM and to test whether this disorder is genetically homogeneous. Methods: We studied 3 MM families with a total of 13 affected subjects. Each patient had a standardized interview and neurologic examination, focusing on the phenomenology and course of the MM. The severity of MM was also assessed. Molecular analysis of DCC was performed in the index cases. In addition, linkage analysis of the DCC locus was performed in a large French family. Results: The clinical expression and course of MM were very similar in all the affected subjects, regardless of DCC mutational status. However, slight intersubject variability in the severity of MM was noted within each family. Onset always occurred in infancy or early childhood, and MM did not deteriorate over time. Motor disability due to MM was mild and restricted to activities that require independent movements of the 2 hands. We found a novel mutation in the DCC gene in an Italian family with MM associated with abnormal ipsilateral corticospinal projection. The DCC locus was excluded in the French family. Conclusion: DCC has a crucial role in the development of corticospinal tracts in humans. Congenital MM is genetically heterogeneous, despite its clinical homogeneity.

Neurological adverse events of new generation sodium blocker antiepileptic drugs. Meta-analysis of randomized, double-blinded studies with eslicarbazepine acetate, lacosamide and oxcarbazepine.

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.

The adverse event profile of lacosamide: A systematic review and meta-analysis of randomized controlled trials

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.

Involvement of the human dorsal premotor cortex in unimanual motor control: an interference approach using transcranial magnetic stimulation

Unilateral movements are enabled through a distributed network of motor cortical areas but the relative contribution from the parts of this network is largely unknown. Failure of this network potentially results in mirror activation of the primary motor cortex (M1) ipsilateral to the intended movement. Here we tested the role of the right dorsal premotor cortex (dPMC) in 11 healthy subjects by disrupting its activity with 20 Hz repetitive transcranial magnetic stimulation (rTMS) whilst the subjects exerted a unilateral contraction of the left first dorsal interosseous (FDI). We found that disruption of right dPMC enhanced mirror activation of the ipsilateral left M1, as probed by motor evoked potential (MEP) amplitude to the right FDI. This was not the case with sham rTMS, when rTMS was directed to the right M1, or with rTMS of the right dPMC but without contraction of the left FDI. Findings suggest that activity in the dPMC contributes to the suppression of mirror movements during intended unilateral movements.

Optically tracked neuronavigation increases the stability of hand-held focal coil positioning: Evidence from “transcranial” magnetic stimulation-induced electrical field measurements

The stability of hand-held coil positioning with neuronavigated versus conventional transcranial magnetic stimulation (TMS) is still underinvestigated. Eleven operators naïve for neuronavigation were asked to position and maintain a figure-of-eight-shaped coil over a dipole probe placed within of a polystyrene reproduction of the human head and scalp, in correspondence of the right primary motor cortex. Ten monophasic magnetic pulses were delivered at 46% maximal stimulator output (MSO) in two different experimental conditions: (1) assisted by an optically tracked neuronavigational system; and (2) without neuronavigation. With neuronavigated stimulation, both standard deviation and coefficient of variation of the voltages induced in the dipole probe were significantly lower than without neuronavigation. Results were confirmed in four operators performing a longer-lasting experiment using 50 magnetic pulses in each condition, at an intensity of at 40% MSO. Findings show that optically tracked neuronavigation improves the stability of focal coil positioning.

Clinical utility of eslicarbazepine: current evidence

Eslicarbazepine acetate (ESL) is a new antiepileptic drug whose mechanism of action is blockade of the voltage-gated sodium channel (VGSC). However, in respect to carbamazepine and oxcarbazepine, the active ESL metabolite (eslicarbazepine) affects slow inactivation of VGSC and has a similar affinity for the inactivated state and a lower affinity for the resting state of the channel. This new antiepileptic drug has been recently approved in Europe (trade name Zebinix) and in the United States (trade name Stedesa) for adjunctive treatment in adult subjects with partial-onset seizures, with or without secondary generalization. Following oral administration, ESL is rapidly and extensively metabolized by hepatic esterases to eslicarbazepine. This active metabolite has a linear pharmacokinetic profile, a low binding to plasma proteins (<40%), and a half-life of 20–24 hours and is mainly excreted by kidneys in an unchanged form or as glucuronide conjugates. ESL is administered once a day and has a low potential for drug–drug interactions. Efficacy and safety of this drug in patients with focal seizures have been assessed in four randomized clinical trials, and responder rates (percentage of patients with a ≥50% improvement of their seizures) ranged between 17% and 43%. Adverse events were usually mild to moderate, and the most common were dizziness, somnolence, diplopia, abnormal coordination, blurred vision, vertigo, headache, fatigue, nausea, and vomiting. ESL may be considered an interesting alternative to current antiepileptic drugs for the treatment of drug-resistant focal epilepsies. Additionally, it is under investigation in children with focal epilepsies, in patients with newly diagnosed focal epilepsies, and also in other neurological and psychiatric disorders.

The adverse event profile of perampanel: meta-analysis of randomized controlled trials

To identify adverse events (AEs) significantly associated with perampanel treatment in double‐blind clinical studies (RCTs). Serious AEs, study withdrawals due to AEs and dose–effect responses of individual AEs were also investigated.