Electrophysiological Activity Prior to Self-initiated Movements is Related to Impulsive Personality Traits.

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.

Relationship between impulsivity traits and awareness of motor intention.

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.

Audio-visual integration effect in lateral occipital cortex during an object recognition task: An interference pilot study.

BACKGROUND: Recent neuroimaging data support the hypothesis of a multisensory interplay at low-level sensory-specific cortex. OBJECTIVE: We used an on-line interference approach by rTMS to investigate the role of the left lateral occipital cortex (LOC) in audio-visual (AV) object recognition process. METHODS: Fifteen healthy volunteers performed a visual identification task of degraded pictures presented alone or simultaneously to coherent or non-coherent sounds. Focal 10-Hz rTMS at an intensity of 100% resting motor threshold was delivered simultaneously to the picture. Two blocks of 60 pictures were randomly displayed in two different experimental conditions: rTMS of the left LOC and over Cz. RESULTS: rTMS of the left LOC produced a worsening of the accuracy compared to rTMS over Cz specifically in the coherent AV condition. CONCLUSION: These data support the view that audio-visual interaction effect may occur at early stage of recognition processing.

Abnormal motor cortex excitability during linguistic tasks in adductor-type spasmodic dysphonia.

In healthy subjects (HS), transcranial magnetic stimulation (TMS) applied during 'linguistic' tasks discloses excitability changes in the dominant hemisphere primary motor cortex (M1). We investigated 'linguistic' task-related cortical excitability modulation in patients with adductor-type spasmodic dysphonia (ASD), a speech-related focal dystonia. We studied 10 ASD patients and 10 HS. Speech examination included voice cepstral analysis. We investigated the dominant/non-dominant M1 excitability at baseline, during 'linguistic' (reading aloud/silent reading/producing simple phonation) and 'non-linguistic' tasks (looking at non-letter strings/producing oral movements). Motor evoked potentials (MEPs) were recorded from the contralateral hand muscles. We measured the cortical silent period (CSP) length and tested MEPs in HS and patients performing the 'linguistic' tasks with different voice intensities. We also examined MEPs in HS and ASD during hand-related 'action-verb' observation. Patients were studied under and not-under botulinum neurotoxin-type A (BoNT-A). In HS, TMS over the dominant M1 elicited larger MEPs during 'reading aloud' than during the other 'linguistic'/'non-linguistic' tasks. Conversely, in ASD, TMS over the dominant M1 elicited increased-amplitude MEPs during 'reading aloud' and 'syllabic phonation' tasks. CSP length was shorter in ASD than in HS and remained unchanged in both groups performing 'linguistic'/'non-linguistic' tasks. In HS and ASD, 'linguistic' task-related excitability changes were present regardless of the different voice intensities. During hand-related 'action-verb' observation, MEPs decreased in HS, whereas in ASD they increased. In ASD, BoNT-A improved speech, as demonstrated by cepstral analysis and restored the TMS abnormalities. ASD reflects dominant hemisphere excitability changes related to 'linguistic' tasks; BoNT-A returns these excitability changes to normal.

" The times they aren't a-changin' " rTMS does not affect basic mechanisms of temporal discrimination: a pilot study with ERPs.

In time processing, the role of different cortical areas is still under investigation. Event-related potentials (ERPs) represent valuable indices of neural timing mechanisms in the millisecond-to-second domain. We used an interference approach by repetitive TMS (rTMS) on ERPs and behavioral performance to investigate the role of different cortical areas in processing basic temporal information. Ten healthy volunteers were requested to decide whether time intervals between two tones (S1-S2, probe interval) were shorter (800ms), equal to, or longer (1200ms) than a previously listened 1000-ms interval (target interval) and press different buttons accordingly. This task was performed at the baseline and immediately after a 15-min-long train of 1-Hz rTMS delivered over the supplementary motor area, right posterior parietal cortex, right superior temporal gyrus, or an occipital control area. Task accuracy, reaction time, and ERPs during (contingent negative variation, CNV) and after the presentation of probe intervals were analyzed. At the baseline, CNV amplitude was modulated by the duration of the probe interval. RTMS had no significant effect on behavioral or ERP measures. These preliminary data suggest that stimulated cortical areas are less crucially involved than other brain regions (e.g. subcortical structures) in the explicit discrimination of auditory time intervals in the range of hundreds of milliseconds.

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

BACKGROUND AND PURPOSE: 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. METHODS: All placebo controlled, double-blind RCTs investigating therapeutic effects of oral perampanel were searched. AEs were assessed for their association with perampanel after exclusion of synonyms, rare AEs and non-assessable AEs. Risk difference (RD) was used to evaluate the association of any AE (99% confidence intervals) and withdrawals or serious AEs (95% confidence intervals) with perampanel. RESULTS: Nine RCTs (five in pharmacoresistant epilepsy and four in Parkinson's disease) were included in our study. Almost 4000 patients had been recruited, 2627 of whom were randomized to perampanel and treated with drug doses of 0.5 mg/day (n = 68), 1 mg/day (n = 65), 2 mg/day (n = 753), 4 mg/day (n = 1017), 8 mg/day (n = 431) or 12 mg/day (n = 293). Serious AEs were not significantly associated with perampanel treatment. The experimental drug was significantly associated with an increased risk of AE-related study withdrawals at 4 mg/day [RD (95% confidence interval) 0.03 (0.00, 0.06)] and 12 mg/day [RD (95% confidence interval) 0.13 (0.07, 0.18)]. Of 15 identified AEs, five (dizziness, ataxia, somnolence, irritability and weight increase) were found to be significantly associated with perampanel and one (seizure worsening) was significantly associated with placebo. CONCLUSIONS: Vestibulocerebellar AEs (dizziness, ataxia), sedative effects (somnolence), irritability and weight increase were significantly associated with perampanel treatment.

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 body's 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.

An integrated fMRI, SEPs and MEPs approach for assessing functional organization in the malformed sensorimotor cortex.

PURPOSE: Malformations of cortical development are often accompanied by an abnormal cortical pattern. Due to its propensity to involve discrete cortical areas, polymicrogyria represents an interesting model for assessing the reorganization of cortical function in relation to the disrupted anatomy. Functional MRI, TMS and SEPs can provide a highly complementary, multimodal approach to map noninvasively the functional rearrangement of sensorimotor functions in the polymicrogyric cortex, and to obtain a coherent modelling. We report here an illustrative case which is included in a patients series under study using a block design 3T fMRI, short-latency SEPs as identified on the basis of their latency, polarity, and scalp distribution and an assessment of the area and volume of the motor maps and the relative position of the center of gravity and hot spot. RESULTS: A 15 years old girl, with drug-resistant epilepsy and left perisylvian polymicrogyria that was part of a large epileptogenic network including also the mesial aspect of the left frontal lobe, exhibited a normal distribution of somatomotor responses in the expected anatomic sites, with a dissociation between motor functions, which were slightly impaired in the malformed hemisphere, and bilaterally normal sensory responses. In this patient, a large resection of epileptogenic zone, sparing eloquent areas as previously identified, should be planned in order to improve seizure outcome. CONCLUSIONS: An integrated fMRI, TMS and SEP mapping approach helps defining the relationship between epileptogenic zones and somatomotor areas. Studies of greater number of patients will be necessary in order to identify the general rules that determine the functional representation in the malformed cortex.

Mild cognitive impairment: loss of linguistic task-induced changes in motor cortex excitability.

BACKGROUND: In amnestic mild cognitive impairment (aMCI), functional neuronal connectivity may be altered, as suggested by quantitative EEG and neuroimaging data. In young healthy humans, the execution of linguistic tasks modifies the excitability of the hand area of the dominant primary motor cortex (M1(hand)), as tested by transcranial magnetic stimulation (TMS). We used TMS to investigate functional connectivity between language-related cortical areas and M1(hand) in aMCI. METHODS: Ten elderly women with aMCI and 10 age-matched women were recruited. All participants were right handed and underwent a neuropsychological evaluation. In the first TMS experiment, participants performed three different tasks: reading aloud, viewing of non-letter strings (baseline), and nonverbal oral movements. The second experiment included the baseline condition and three visual searching/matching tasks using letters, geometric shapes, or digits as target stimuli. RESULTS: In controls, motor evoked potentials (MEP) elicited by suprathreshold TMS of the left M1(hand) were significantly larger during reading aloud (170% baseline) than during nonverbal oral movements, whereas no difference was seen for right M1(hand) stimulation. Similarly, MEP elicited by left M1(hand) stimulation during letter and shape searching/matching tasks were significantly larger compared to digit task. In contrast, linguistic task performance did not produce any significant MEP modulation in patients with aMCI, although neuropsychological evaluation showed normal language abilities. CONCLUSIONS: Findings suggest that functional connectivity between the language-related brain regions and the dominant M1(hand) may be altered in amnestic mild cognitive impairment. Follow-up studies will reveal whether transcranial magnetic stimulation application during linguistic tasks may contribute to characterize the risk of conversion to Alzheimer disease.

Central nervous system adverse effects of new antiepileptic drugs. A meta-analysis of placebo-controlled studies.

OBJECTIVE: Systematic review and meta-analysis of the most frequent treatment-emergent central nervous system adverse events (CNS AEs) of new antiepileptic drugs (AEDs) from double-blind, add-on, placebo-controlled studies conducted in adult epileptic patients and identification of dose-adverse effect relationships. METHODS: Trial reports found by searching Medline and journals. Outcome was the number of patients complaining of treatment-emergent CNS AEs. Sixteen predefined CNS AEs were considered. Risk differences (RDs) were calculated for individual studies and summary statistics estimated using the random effect model. Predefined CNS AEs in patients treated with active drug (broken down into dose levels) or placebo were extracted and the RDs (95% CI) for CNS AEs were calculated. RESULTS: Thirty-six suitable studies identified. No meta-analysis was possible for oxcarbazepine and tiagabine (only one study each included). For these drugs RDs were calculated from single studies. Gabapentin was significantly associated with somnolence 0.13 (0.06-0.2) and dizziness 0.11 (0.07-0.15); lamotrigine with dizziness 0.11 (0.05-0.17), ataxia 0.12 (0.01-0.24) and diplopia 0.12 (0.00-0.24); levetiracetam with somnolence 0.06 (0.01-0.11); pregabalin with somnolence 0.11 (0.07-0.15), dizziness 0.22 (0.16-0.28), ataxia 0.10 (0.06-0.14) and fatigue 0.04 (0.01-0.08); topiramate with somnolence 0.09 (0.04-0.14), dizziness 0.06 (0.00-0.11), cognitive impairment 0.14 (0.06-0.22) and fatigue 0.06 (0.01-0.12); zonisamide with somnolence 0.06 (0.02-0.11) and dizziness 0.06 (0.00-0.12). The dose-response relationship was analysed only for those CNS AEs significantly associated with the AED. CONCLUSIONS: No comparison between drugs was possible. One CNS AE was significantly more frequent for levetiracetam, two for zonisamide and gabapentin, three for lamotrigine and four for pregabalin and topiramate.

Neurophysiology of unimanual motor control and mirror movements.

In humans, execution of unimanual motor tasks requires a neural network that is capable of restricting neuronal motor output activity to the primary motor cortex (M1) contralateral to the voluntary movement by counteracting the default propensity to produce mirror-symmetrical bimanual movements. The motor command is transmitted from the M1 to the contralateral spinal motoneurons by a largely crossed system of fast-conducting corticospinal neurons. Alteration or even transient dysfunction of the neural circuits underlying movement lateralization may result in involuntary mirror movements (MM). Different models exist, which have attributed MM to unintended motor output from the M1 ipsilateral to the voluntary movement, functionally active uncrossed corticospinal projections, or on a combination of both. Over the last two decades, transcranial magnetic stimulation (TMS) proved as a valuable, non-invasive neurophysiological tool to investigate motor control in healthy volunteers and neurological patients. The contribution of TMS and other non-invasive electrophysiological techniques to characterize the neural network responsible for the so-called 'non-mirror transformation' of motor programs and the various mechanisms underlying 'physiological' mirroring, and congenital or acquired pathological MM are the focus of this review.

Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies.

The system involving angiopoietin-2 (Ang-2) and its receptor, Tie-2, appears to play an important role not only in tumor angiogenesis, but also in the biology of haematological and non-haematological malignancies. In the present study we evaluated the serum levels of soluble Ang-2 (sAng-2) and soluble Tie-2 (sTie-2) in patients with haematological malignancies. Measurements were carried out in 15 patients with chronic myeloid leukaemia (CML), 25 with essential thrombocythemia (ET), 24 with multiple myeloma (MM) and six with monoclonal gammopathy of undetermined significance (MGUS). In addition, we correlated the levels of angiopoietins with known prognostic factors. sAng-2 and sTie-2 were quantified with enzyme-linked immunosorbent assay (ELISA). In patients with CML and MM the levels of sAng-2 were significantly higher (1686.53 +/- 936.41 pg/mL and 1917.82 +/- 1427 pg/mL, respectively) than in controls (n = 15; 996.096 +/- 414.65 pg/mL) (P < 0.01). In patients with MM sAng-2 levels were significantly increased with increasing stage of disease, from stage I to stage III (P < 0.03) and presented a trend of correlation with Beta2-microglobulin levels (r = 0.317) and grade of bone involvement. Furthermore, the levels of sAng-2 determined after 6 months of chemotherapy in CML patients were significantly lower than at diagnosis in the patients who achieved haematological remission. Circulating sTie-2 levels were increased in patients with ET (17.5 +/- 9.2 vs 9 +/- 3.5 ng/mL; P < 0.01) and in those with CML (16.29 +/- 8.7 ng/mL; P < 0.04). In conclusion, abnormal levels of sAng-2 and sTie-2 are present in some haematological malignancies. These markers may play a role in the pathophysiology of these conditions and their progression.

Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies?

OBJECTIVE: A review of long-term open-label studies was performed with the aim of detecting differences in efficacy and/or tolerability of new antiepileptic drugs (AEDs). METHODS: From more than 500 open studies conducted to evaluate the efficacy and tolerability of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), pregabalin (PGB), tiagabine (TGB), topiramate (TPM) or zonisamide (ZNS), we selected all studies that reported or allowed us to calculate the number of patients who achieved seizure freedom for 6 months and/or the number of patients withdrawing for adverse effects and/or the number or percentage of patients continuing treatment after 1 year. RESULTS: No studies were found in which this information was available for OXC, PGB, TGB or ZNS. The number of patients who achieved seizure freedom for 6 months was reported in four studies each for GBP and TPM, five studies for LTG, and eight studies for LEV. The best efficacy profile using this end point was found for LEV, followed by TPM, LTG, and GBP. Twenty-two studies reported the number of patients withdrawing due to adverse effects. LEV was the best-tolerated AED, a little ahead of LTG, and significantly better than GBP or TPM . TPM was by far the least well-tolerated drug. Information concerning patients continuing treatment after 1 year was reported in two GBP studies, two TPM studies, six LEV studies and five LTG studies. GBP had a very low retention rate (between 20% and 25% of patients continued the drug), while TPM and LTG had a retention rate of 40-60% and LEV had a retention rate of 60-75%. CONCLUSION: One limitation of these rankings is that their statistical value is limited because of the indirect nature of the comparisons. Anyhow, this review covers the main studies published thus far on this subject and provides full updated information on the current literature about these drugs.

Role of the right dorsal premotor cortex in "physiological" mirror EMG activity.

A distributed cortical network enables the lateralization of intended unimanual movements, i.e., the transformation from a default mirror movement to a unimanual movement. Little is known about the exact functional organization of this "non-mirror transformation" network. Involvement of the right dorsal premotor cortex (dPMC) was suggested because its virtual lesion by high-frequency repetitive transcranial magnetic stimulation (rTMS) increased the excitability of the left primary motor cortex (M1) during unilateral isometric contraction of a left hand muscle (Cincotta et al., Neurosci Lett 367: 189-93, 2004). However, no behavioural effects were observed in that experimental protocol. Here we tested behaviourally twelve healthy volunteers to find out whether focal disruption of the right dPMC by "off-line" One Hz rTMS (900 pulses, 115% of resting motor threshold) enhances "physiological" mirroring. This was measured by an established protocol (Mayston et al., Ann Neurol 45: 583-94, 1999) that quantifies the mirror increase in the electromyographic (EMG) level in the isometrically contracting abductor pollicis brevis (APB) muscle of one hand during brief phasic contractions performed with the APB of the other hand. Mirroring in the right APB significantly increased after real rTMS of the right dPMC. In contrast, no change in mirroring was seen with sham rTMS of the right dPMC, real rTMS of the right M1, or real rTMS of the left dPMC. These findings strongly support the hypothesis that the right dPMC is part of the non-mirror transformation cortical network.

Modulatory effects of high-frequency repetitive transcranial magnetic stimulation on the ipsilateral silent period.

In healthy subjects, suprathreshold repetitive transcranial magnetic stimulation (rTMS) at frequencies >2 Hz prolongs the cortical silent period (CSP) over the course of the train. This progressive lengthening probably reflects temporal summation of the inhibitory interneurons in the stimulated primary motor cortex (M1). In this study, we tested whether high-frequency rTMS also modulates the ipsilateral silent period (ISP). In nine normal subjects, suprathreshold 10-pulse rTMS trains were delivered to the right M1 at frequencies of 3, 5, and 10 Hz during maximal isometric contraction of both first dorsal interosseous muscles. At 10 Hz, the second pulse of the train increased the area of the ISP; the other stimuli did not increase it further. During rTMS at 3 and 5 Hz, the ISP remained significantly unchanged. Control experiments showed that 10-Hz rTMS delivered at subthreshold intensity also increased the ISP. rTMS over the hand motor area did not facilitate ISPs in the biceps muscles. Finally, rTMS-induced ISP facilitation did not outlast the 10-Hz rTMS train. These findings suggest that rTMS at a frequency of 10 Hz potentiates the interhemispheric inhibitory mechanisms responsible for the ISP, partly through temporal summation. The distinct changes in the ISP and CSP suggest that rTMS facilitates intrahemispheric and interhemispheric inhibitory phenomena through separate neural mechanisms. The ISP facilitation induced by high-frequency rTMS is a novel, promising tool to investigate pathophysiological abnormal interhemispheric inhibitory transfer in various neurological diseases.

Osteoprotegerin and bone mineral density in hemodiafiltration patients.

A newly identified cytokine, osteoprotegerin (OPG) appears to be involved in the regulation of bone remodeling. In vitro studies suggest that OPG, a soluble member of the TNF receptor family of proteins, inhibits osteoclastogenesis by interrupting the intercellular signaling between osteoblastic stromal cells and osteoclast progenitors. As patients with chronic renal failure (CRF) often have renal osteodystrophy (ROD), we investigated the role of osteoprotegerin (OPG) in ROD, and investigated whether there was any relationship between serum OPG, intact parathyroid (PTH) (iPTH), vitamin D, and trabecular bone. Serum OPG combined with iPTH might be a useful tool in the noninvasive diagnosis of ROD, at least in cases in which the range of PTH values compromises reliable diagnosis. Thirty-six patients on maintenance hemodiafiltration (HDF) and a control group of 36 age and sex matched healthy subjects with no known metabolic bone disease were studied. The following assays were made on serum: iPTH, osteocalcin (BGP), bone alkaline phosphatase, 25(OH)-cholecalciferol, calcium, phosphate, OPG, IGF-1, estradiol, and free testosterone. Serum Ca++, P, B-ALP, BGP, IGF-1, iPTH, and OPG levels were significantly higher in HDF patients than in controls, while DXA measurements and quantitative ultrasound (QUS) parameters were significantly lower. On grouping patients according to their mean OPG levels, we observed significantly lower serum IGF-1, vitamin D3 concentrations, and lumbar spine and hip bone mineral density in the high OPG groups. No correlation was found between OPG and bone turnover markers, whereas a negative correlation was found between serum OPG and IGF-1 levels (r=-0.64, p=0.032). Serum iPTH concentrations were positively correlated with bone alkaline phosphatase (B-ALP) (r=0.69, p=0.038) and BGP (r=0.92, p<0.001). The findings made suggest that an increase in OPG levels may be a compensatory response to elevated bone loss. The low bone mineral density (BMD) levels found in the high OPG group might have been due to the significant decrease in serum IGF-1 and vitamin D3 observed. In conclusion, the findings made in the present study demonstrate that increased OPG in hemodiafiltration patients is only partly due to decreased renal clearance. As it may partly reflect a compensatory response to increased bone loss, this parameter might be helpful in the identification of patients with a marked reduction in trabecular BMD.

Physical interactions between induced electrical fields can have substantial effects on neuronal excitation during simultaneous TMS of two brain areas.

OBJECTIVE: To analyse the interactions between simultaneous or nearly simultaneous focal transcranial magnetic stimulation (TMS) of the motor cortex hand area (M1hand) of both hemispheres. METHODS: In 7 healthy subjects, motor evoked potential (MEP) amplitude and cortical silent period (CSP) duration were elicited in the right hand by bihemispheric focal TMS of M1hand (8-shaped coils, monophasic current waveform, stimulus intensity 120% above motor threshold, TMS of right M1hand preceding TMS of left M1hand by 0-1000 micros), or by unilateral TMS of left M1hand alone. A dipole probe was used to measure the physical interactions between the two stimulating coils. RESULTS: Bihemispheric TMS markedly decreased MEP and CSP at intervals of 0 and 50 micros compared to unilateral TMS, whereas both measures increased at the interval of 150 micros. The dipole probe experiments showed that the physical interactions between the electrical fields of the two coils entirely explained the MEP and CSP findings, but only under the assumption that excitation of M1hand is not point-focal but extends over several centimetres. CONCLUSIONS: First, simultaneous focal TMS of distant brain sites may result in marked 'distortion' of brain excitation through physical interaction between the induced electrical fields. Second, these findings support the notion that excitation of human M1hand is relatively non-focal, even if a 'focal' stimulating coil and low stimulus intensity are used. SIGNIFICANCE: Potentially marked physical interaction between induced electrical fields must be taken into account when testing or disrupting distant brain sites with simultaneous focal TMS.

Adverse motor effects induced by antiepileptic drugs.

Cognitive effects of anti-epileptic drugs (AEDs) have been already extensively reported. In contrast, motor disturbances, frequently induced by these drugs, have not received similar attention. We review subjective and objective adverse motor effects of traditional and new AEDs. We discuss the methodological issues caused by the heterogeneous sources of information on drug adverse effects (controlled clinical studies, open studies, and case reports). We describe specific disturbances (vestibulocerebellar, dyskinesias, parkinsonism, tics, myoclonus, and tremor) as the effects of different AEDs on distinct motor circuitries. Finally, we summarize the role of sophisticated technical studies which provide a valuable insight into the specific or subtle effects of AEDs on the central nervous system.