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Despite a huge effort of the scientific community, the functioning of Long-Term Memory (LTM) processes is still debated and far from being elucidated. Functional and neurophysiological data point to an involvement of Dorsolateral Prefrontal Cortex (DLPFC) in both encoding and retrieval phases. However, the recently proposed Explicit/Implicit Memory Encoding and Retrieval (EIMER) model proposes that LTM at the encoding phase consists of anatomically and chronologically different sub-phases. On this basis, we aimed to investigate the role of right DLPFC during a late-encoding phase by means of low-frequency rTMS. Thirty right-handed healthy subjects were divided into three experimental groups. Inhibitory rTMS was applied over right-DLPFC immediately after the encoding phase (Late-Encoding Group) or before recognition phase (Pre-Recognition Group), 24 h after, of an LTM task. Both groups also received sham stimulation during the non-target phase, while the third group (Sham Group) received only sham stimulation in both phases. The Late-Encoding Group collected a lower number of correct responses compared with Sham Group (p = 0.00), while Pre-Retrieval Group increased accuracy as compared to the Sham Group (p = 0.0). rTMS-inhibition of the right DLPFC seems able to interfere with LTM memory performances when delivered at a late stage of the encoding phase, with opposite effects at the pre-retrieval phase.

BACKGROUND: The management of epilepsy in older adults has become part of daily practice because of an aging population. Older patients with epilepsy represent a distinct and more vulnerable clinical group as compared with younger patients, and they are generally under-represented in randomized placebo-controlled trials. Real-world studies can therefore be a useful complement to characterize the drug's profile. Brivaracetam is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A and approved as adjunctive therapy for focal seizures in adults with epilepsy. OBJECTIVE: The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive brivaracetam in older patients (≥65 years of age) with epilepsy treated in a real-world setting. METHODS: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a 12-month retrospective multicenter study including adult patients prescribed adjunctive brivaracetam. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events and the incidence of adverse events. Data were compared for patients aged ≥65 years of age ('older') vs those aged

Objective: Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy and accounts for about 10-15% of all newly diagnosed epilepsy cases. However, evidence about the clinical profile of antiseizure medications in the PSE setting is currently limited. Brivaracetam (BRV) is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A. The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive BRV in patients with PSE treated in a real-world setting. Methods: This was a subgroup analysis of patients with PSE included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). The BRIVAFIRST was a 12-month retrospective, multicentre study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure‐freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Results: Patients with PSE included in the BRIVAFIRST were 75 and had a median age of 57 (interquartile range, 42-66) years. The median daily doses of BRV at 3, 6, and 12 months from starting treatment were 100 (100-150) mg, 125 (100-200) mg and 100 (100-200) mg, respectively. At 12 months, 32 (42.7%) patients had a reduction in their baseline seizure frequency by at least 50%, and the seizure freedom rates was 26/75 (34.7%). During the 1-year study period, 10 (13.3%) patients discontinued BRV. The reasons of treatment withdrawal were insufficient efficacy in 6 (8.0%) patients and poor tolerability in 4 (5.3%) patients. Adverse events were reported by 13 (20.3%) patients and were rated as mild in 84.6% and moderate in 15.4% of cases. Significance: Adjunctive BRV was efficacious and generally well-tolerated when used in patients with PSE in clinical practice. Adjunctive BRV can be a suitable therapeutic option for patients with PSE.

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32-56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy.

We evaluated the effects of transcranial random noise stimulation (tRNS) on fatigue in 17 subjects with relapsing–remitting multiple sclerosis with low physical disability. Two different patient groups underwent real or sham stimulation for 10days, targeting the primary motor cortex of the dominant side or contralateral to the most compromised limb. In the ‘real group’, beneficial effects were observed using the Modified Fatigue Impact Scale (p = 0.04; physical subscale: p = 0.03), the subscales ‘change in health’ (p = 0.006) and ‘role limitations due to physical problems’ (p = 0.001) of the Multiple Sclerosis Quality of Life-54, and by assessing the patient impression of perceived fatigue (p = 0.005).

Inherited neuromuscular disorders (INMD) are a heterogeneous group of rare diseases that involve muscles, motor neurons, peripheral nerves or the neuromuscular junction. Several different lab abnormalities have been linked to INMD: sometimes they are typical of the disorder, but they usually appear to be less specific. Sometimes serum biomarkers can point out abnormalities in presymtomatic or otherwise asymptomatic patients (e.g., carriers). More often a biomarker of INMD is evaluated by multiple clinicians other than expert in NMD before the diagnosis, because of the multisystemic involvement in INMD. The authors performed a literature search on biomarkers in inherited neuromuscular disorders to provide a practical approach to the diagnosis and the correct management of INMD. A considerable number of biomarkers have been reported that support the diagnosis of INMD, but the role of an expert clinician is crucial. Hence, the complete knowledge of such abnormalities can accelerate the diagnostic workup supporting the referral to specialists in neuromuscular disorders.

Gambling disorder (GD) is a psychiatric disease that has been recently classified as a behavioural addiction. So far, a very few studies have investigated the alteration of functional connectivity in GD patients, thus the concrete interplay between relevant function-dependent circuitries in such disease has not been comprehensively assessed. The aim of this research was to investigate resting-state functional connectivity in GD patients, searching for a correlation with GD symptoms severity. GD patients were assessed for gambling behaviour, impulsivity, cognitive distortions, anxiety and depression, in comparison with healthy controls (HC). Afterwards, they were assessed for resting-state functional magnetic resonance imaging; functional connectivity was assessed through a data-driven approach, by using independent component analysis. The correlation between gambling severity and the strength of specific resting-state networks was also investigated. Our results show that GD patients displayed higher emotional and behavioural impairment than HC, together with an increased resting state functional connectivity in the network including anterior cingulate cortex, the caudate nucleus and nucleus accumbens, and within the cerebellum, in comparison with the control group. Moreover, a significant correlation between behavioural parameters and the strength of the resting-state cerebellar network was found. Overall, the functional alterations in brain connectivity involving the cerebellum observed in this study underpin the emotional and behavioural impairment recorded in GD patients. This evidence suggests the employment of novel neuromodulatory therapeutic approaches involving specific and salient targets such as the cerebellum in addictive disorders.

We evaluated the combined use of transcranial random noise stimulation (tRNS) with the Graded Repetitive Arm Supplementary Program (GRASP) in sub-acute ischemic stroke patients suffering from arm impairment. Eighteen ischemic stroke patients with upper limb disability were randomly assigned to either the GRASP + tRNS or GRASP + Sham stimulation group. Fugl-Meyer Assessment-Upper extremity (FMA-UE) was performed to evaluate upper limb impairment before treatment (T0), after the last stimulation (T1) and after 30 days (T2). At T1 and T2, beneficial effects in the tRNS group correlated with better FMA-UE score than sham stimulation group (p

The observation of an action modulates motor cortical outputs in specific ways, in part through mediation of the mirror neuron system. Sometimes we infer a meaning to an observed action based on integration of the actual percept with memories. Here, we conducted a series of experiments in healthy adults to investigate whether such inferred meanings can also modulate motor cortical outputs in specific ways. We show that brief observation of a neutral stimulus mimicking a hand does not significantly modulate motor cortical excitability (Study 1) although, after prolonged exposure, it can lead to a relatively nonspecific modulation (Study 2). However, when such a neutral stimulus is preceded by exposure to a hand stimulus, the latter appears to serve as a prime, perhaps enabling meaning to the neutral stimulus, which then modulates motor cortical excitability in accordance with mirror neuron-driving properties (Studies 2 and 3). Overall results suggest that a symbolic value ascribed to an otherwise neutral stimulus can modulate motor cortical outputs, revealing the influence of top-down inputs on the mirror neuron system. These findings indicate a novel aspect of the human mirror neuron system: an otherwise neutral stimulus can acquire specific mirror neuron-driving properties in the absence of a direct association between motor practice and perception. This significant malleability in the way that the mirror neuron system can code otherwise meaningless (i.e. arbitrarily associated) stimuli may contribute to coding communicative signals such as language. This may represent a mirror neuron system feature that is unique to humans.

A number of researchers have proposed that the premotor and motor areas are critical for the representation of words that refer to actions, but not objects. Recent evidence against this hypothesis indicates that the left premotor cortex is more sensitive to grammatical differences than to conceptual differences between words. However, it may still be the case that other anterior motor regions are engaged in processing a word's sensorimotor features. In the present study, we used singleand paired-pulse transcranial magnetic stimulation to test the hypothesis that left primary motor cortex is activated during the retrieval of words (nouns and verbs) associated with specific actions. We found that activation in the motor cortex increased for action words compared with non-action words, but was not sensitive to the grammatical category of the word being produced. These results complement previous findings and support the notion that producing a word activates some brain regions relevant to the sensorimotor properties associated with that word regardless of its grammatical category.

Objective: To investigate the modulatory effect of a subthreshold low frequency repetitive transcranial magnetic stimulation (rTMS) train on motor cortex excitability. Methods: The study consisted of two separate experiments. Subjects received a 10 min long subthreshold 1Hz rTMS train. In the first experiment, (single pulse paradigm), cortical excitability was assessed by measuring the amplitude of motor evoked potentials (MEPs) before and after the rTMS train. In the second experiment, a paired pulse paradigm was employed. Results: Corticospinal excitability, as measured by the MEP amplitude, was reduced by the rTMS train (experiment 1), with a significant effect lasting for about 10 min after the train completion. There was notable inter-individual as well as intra-individual variability in the effect. rTMS produced a significant decrease in intra-cortical facilitation as measured by the paired pulse paradigm (experiment 2). This effect lasted for up to 15 min following the train. Intra-cortical inhibition was not significantly affected. Conclusions: Subthreshold low frequency rTMS depresses cortical excitability beyond the duration of the train. This effect seems primarily due to cortical dysfacilitation. These results have implications on the therapeutic use of rTMS. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

The role of tactile information of the hand in the control of reaching to grasp movements was investigated. The kinematics of both reaching (or transport) and grasp components were studied in healthy subjects in two experimental conditions. In one condition (control condition) subjects were required to reach and grasp an object that could have two sizes and that could be located at two distances from the viewer. In the other condition (anaesthesia condition) the same movements were executed, but anaesthesia was provided to the subjects' fingertips. In both conditions vision of the hand was prevented during movement. Anaesthesia affected mainly the kinematics of the first phase of grasping, that is, the finger-opening phase. This phase was lengthened and maximal finger aperture increased. In contrast, the duration of the successive phase (finger-closure) was poorly modified. The reaching component was also impaired by anaesthesia. Although the total extent of hand path and the spatial relations between the finger aperture and closure phases did not change between the two conditions, hand path variability increased. This occurred during transport deceleration phase and after the increase in variability of finger path. In addition, the whole movement was slowed down. The results of the present experiment suggest that tactile signals at the beginning and at the end of movement can be used to compute grasp time and to optimise grasp temporal parameters. Alternatively, signals from tactile receptors can be involved in encoding the position sense of the fingers. When this input is lacking, the control of grasp and in particular that of finger-opening phase can be impaired. Finally, the effect of the grasp impairment on the reaching component supports the notion that the coordination between reaching and grasping involves the whole temporal course of the two components.

Transient topographical amnesia (TTA) is the temporary inability to find one's way in familiar or unfamiliar surroundings due to the inability to use well known environmental landmarks for route finding. The syndrome has not been described as having any obvious aetiology and has been thought to be caused by a vascular deficit in right hemispheric structures which are crucial for topographic recognition, i.e. parietal association and parahippocampal cortex. The patient described in the present study complained of several critical episodes of TTA and tonic rigidity of the left limbs. Neuropsychological assessment was normal except for a deficit in spatial memory tasks. Magnetic resonance (MR) imaging of the brain showed an angioma at the border of areas 24d and 23 of the right cingulate cortex. Because area 23 is strategically located in a network that links the parietal associative (area 7a) and parahippocampal cortices, and because these cortical areas are involved in topographical orienting processes, we suggest that a transient functional inactivation of the network caused by epileptic discharges spreading from the damaged cingulate cortex towards the parahippocampal and parietal association cortex could account for the spatial disorder. Similar discharges spreading from area 24d towards the primary motor cortex and/or the spinal cord could account for the episodes of tonic rigidity of the left limbs.

The observation of an action modulates motor cortical outputs in specific ways, in part through mediation of the mirror neuron system. Sometimes we infer a meaning to an observed action based on integration of the actual percept with memories. Here, we conducted a series of experiments in healthy adults to investigate whether such inferred meanings can also modulate motor cortical outputs in specific ways. We show that brief observation of a neutral stimulus mimicking a hand does not significantly modulate motor cortical excitability (Study 1) although, after prolonged exposure, it can lead to a relatively nonspecific modulation (Study 2). However, when such a neutral stimulus is preceded by exposure to a hand stimulus, the latter appears to serve as a prime, perhaps enabling meaning to the neutral stimulus, which then modulates motor cortical excitability in accordance with mirror neuron-driving properties (Studies 2 and 3). Overall results suggest that a symbolic value ascribed to an otherwise neutral stimulus can modulate motor cortical outputs, revealing the influence of top-down inputs on the mirror neuron system. These findings indicate a novel aspect of the human mirror neuron system: an otherwise neutral stimulus can acquire specific mirror neuron-driving properties in the absence of a direct association between motor practice and perception. This significant malleability in the way that the mirror neuron system can code otherwise meaningless (i.e. arbitrarily associated) stimuli may contribute to coding communicative signals such as language. This may represent a mirror neuron system feature that is unique to humans.

In the present study we aimed to explore by means of repetitive transcranial magnetic stimulation (rTMS) the reciprocal influences between prefrontal cortex (PFC) and premotor cortex (PMC). Subjects were asked to observe on a computer monitor different pictures representing manipulations of different kind of tools. They had to produce a movement (go condition) or to keep the resting position (no-go condition) at the appearance of different cue signals represented by different colors shown alternatively on the hands manipulating the tools or on the picture background. Motor evoked potentials (MEPs) were collected at the offset of the visual stimuli before and after a 10 minute, 1 Hz rTMS train applied to the dorsolateral PFC (Experiment 1), to the PMC (Experiment 2) or to the primary motor cortex (Experiment 3). Following rTMS to the PFC, MEPs increased in the go condition when the cue for the go command was presented on the hand. In contrast, following rTMS to the PMC, in the same condition, MEPs were decreased. rTMS to the primary motor cortex did not produce any modulation. Results are discussed according to the presence of a visual-motor matching system in the PMC and to the role of the PFC in the attention-related processes. We hypothesize that the perceptual analysis for action selection within the PFC was modulated by rTMS and its temporary functional inactivation in turn influenced the premotor areas for motor programming.

We studied the time-course of a levodopa oral bolus effects on the kinematics of patients affected by a mild akinetic-rigid form of idiopathic Parkinson's disease (PD). Eleven PD patients were evaluated: a) in OFF-state, that is before their first medication or after its withdrawal, b) in ON-state, that is at 1/2, 1, 2, 3, 4, 5, 6, 24, 30 and 48 hours after the administration of 250 mg of levodopa plus 25mg of carbidopa. The main kinematics (i. e.movement time, peak of velocity, peak of acceleration and peak of deceleration) of pointing movements to six target-stimuli placed on the horizontal plane of a table were recorded. Clinical conditions were assessed according to the Motor Examination section of the Unified Parkinson's Disease Rating Scale. The levopoda bolus had stable clinical effects only within the first six hours from its administration. The decline of the clinical response was marked by the changes of peak acceleration whereas other kinematics (i. e. movement time and the peak of velocity) changed also in the late observations (24, 30 and 48 hours after drug intake). The dissociation between the persistent improvement on movement time on peak velocity and the rapid deterioration of levodopa effects on early kinematics (i. e. peak acceleration) could be accounted for by a progressive decline in movement programming.

Using transcranial magnetic stimulation, we explored the properties of premotor mirror neurons during the passive observation of a reaching-grasping movement in human subjects. Two different experiments were run using video-clips as visual stimuli. Video-clips showed a normally performed (control stimulus) or an anomalous reaching-grasping movement executed by delaying the time of the appearance of the maximal finger aperture (experiment 1), or substituting it with an unpredictable closure (experiment 2). Motor evoked potentials were recorded at different time-points during the observation of the video-clips. Profiles of cortical excitability were drawn and compared with the kinematic profiles of the corresponding movement. Passive observation of the natural movement evoked a profile of cortical excitability that is in concordance with the timing of the kinematic profile of the shown finger movements. Observation of the uncommon movements did not exert any modulation (experiment 1) or evoked an activity that matched, at the beginning, the modulation obtained with observation of the natural movement (experiment 2). Results show that the resonant motor plan is loaded as whole at the beginning of observation and once started tends to proceed to its completion regardless of changes to the visual cues. The results exclude the possibility of a temporal fragmentation of the resonant plan, because activation of different populations of mirror neurons for each phase of the ongoing action. They further support the notion of the role of the mirror system as neural substrate for the observing-execution matching system and extend the current knowledge regarding mechanisms that trigger the internal representation of an action.

Transcranial magnetic stimulation (TMS) is a non-invasive technique that uses the principle of electromagnetic induction to generate currents in the brain via pulsed magnetic fields. The magnitude of such induced currents is unknown. In this study we measured the TMS induced current densities in a patient with implanted depth electrodes for epilepsy monitoring. A maximum current density of 12 microA/cm2 was recorded at a depth of 1 cm from scalp surface with the optimum stimulation orientation used in the experiment and an intensity of 7% of the maximal stimulator output. During TMS we recorded relative current variations under different stimulating coil orientations and at different points in the subject's brain. The results were in accordance with current theoretical models. The induced currents decayed with distance form the coil and varied with alterations in coil orientations. These results provide novel insight into the physical and neurophysiological processes of TMS.

We explored the temporal dynamics of parietal and prefrontal cortex involvement in verbal working memory employing single-pulse transcranial magnetic stimulation (TMS). In six healthy volunteers the left or right inferior parietal and prefrontal cortex was stimulated with the aid of a frameless stereotactic system. TMS was applied at 10 different time points 140-500 ms into the delay period of a two-back verbal working memory task. A choice reaction task was used as a control task. Interference with task accuracy was induced by TMS earlier in the parietal cortex than in the prefrontal cortex and earlier over the right than the left hemisphere. This suggests a propagation of information flow from posterior to anterior cortical sites converging in the left prefrontal cortex. Significant interference with reaction time was observed after 180 ms with left prefrontal cortex stimulation. These effects were not observed in the control task, underlining the task specificity of our results. We propose that the interference with right-sided prefrontal cortex stimulation leads to impaired performance due to disturbed input into the left prefrontal cortex, whereas left-sided TMS interferes directly with the final information processing. Left- and right-sided brain areas might be involved in parallel processing of semantic and object features of the stimuli, respectively. © 2003 Elsevier Science (USA). All rights reserved.

The aims of this study were to: (1) assess the effects of repetitive transcranial magnetic stimulation (rTMS) on brain activity in depressed patients as measured by single photon emission tomography (SPECT); (2) evaluate the predictive value of brain SPECT on the antidepressant efficacy of rTMS. Patients (n=17) received 1600 rTMS stimuli at a rate of 10 Hz, 5 days per week for 2 weeks to the left dorsolateral prefrontal cortex. Whole brain SPECT data were acquired using Tc99m-Bicisate. Regional cerebral blood flow (rCBF) was correlated with the % change in the 28-item Hamilton Depression Rating Scale Score (Δ-HDRS) and a semiquantitative region of interest (ROI) analysis was conducted. Prior to rTMS there was a significant left-right asymmetry favoring the right, whereas 2 weeks after the rTMS treatment this asymmetry was reversed. The rCBF in limbic structures was negatively correlated with the outcome and rCBF in several neocortical areas was positively correlated. Brain SPECT can provide information about mechanisms of action of rTMS and may have predictive value for the antidepressant efficacy of rTMS. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Objectives: Previous studies have evaluated the variability of motor thresholds (MTs) and amplitude of motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) within and across individuals. Here we evaluate the reproducibility and inter-hemispheric variability of measures of cortical excitability using the 'conventional' paired-pulse (PP) TMS technique. Methods: We studied PP curves of the left and right hemisphere in 10 healthy subjects on two separate days 2 weeks apart. The inter-stimulus intervals studied were 1, 3, 6, 8, 10 and 12 ms with the conditioning stimulus being 80% of the resting MT, and a single test stimulus producing MEPs of approximately 0.8 mV peak-to-peak amplitude. Results: As a group, the PP curves of the left and right hemispheres, and of Day1 and Day2 were not significantly different. The intracortical inhibition (ICI), but not the intracortical facilitation, showed a good correlation across days within the individuals. Conclusions: Cortical excitability, particularly ICI, measured by PP TMS shows no inter-hemispheric asymmetry and is reproducible within individuals. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

The functional organization of working memory (WM) in the human prefrontal cortex remains unclear. Storage and processing functions might be segregated in ventral and dorsal areas of the prefrontal cortex, respectively. If so, storage functions might be spared, irrespective of informational domain, following damage or dysfunction in dorsolateral areas. Alternatively, WM and prefrontal function in general might be segregated according to informational domains (e.g. spatial versus object-based information). In the present study we used repetitive transcranial magnetic stimulation (rTMS) to directly test these competing hypotheses. We applied rTMS to transiently and selectively disrupt the function of the dorsomedial, dorsolateral or ventral prefrontal cortex in normal human volunteers performing either a spatial or a face-recognition delayed-response task. Performance in the spatial task was impaired by rTMS of the dorsomedial prefrontal cortex. Performance in the face-recognition (non-spatial) task was impaired by rTMS of the ventral prefrontal cortex. Transient disruption of the dorsolateral prefrontal cortex affected performance in both tasks. These findings provide evidence of domain-specific segregation of WM functions in widely separated areas of prefrontal cortex.

Repetitive transcranial magnetic stimulation (rTMS) allows the modulation of intra-cortical excitability and may therefore affect the descending control of spinal excitability. We applied rTMS at subthreshold intensity and 1 Hz frequency for 10 min to the left primary motor cortex representation of the flexor carpi radialis muscle (FCR) in 10 subjects and assessed the H and M responses to median nerve stimulation before and after the rTMS. Following rTMS, H wave thresholds significantly reduced by ∼20%. Maximal H but not M wave amplitude significantly increased over the baseline, so that H/M amplitude ratio was increased by 41%. Sham stimulation did not induce any noticeable change in M or H waves. Slow rTMS might facilitate monosynaptic spinal cord reflexes by inhibiting the cortico-spinal projections modulating spinal excitability. © 2001 Lippincott Williams & Wilkins.

Objective: To investigate the intracortical inhibitory and excitatory systems in the motor cortical representation of upper and lower facial muscles. Methods: Paired-pulse transcranial magnetic stimulation (TMS) was applied to 7 healthy volunteers, with the interstimulus interval (ISI) between the conditioning stimulus (CS) and test stimulus, varied from 1 to 20 ms. CS was set at 90% of motor threshold. Muscle evoked potentials (MEPs) were recorded from first dorsal interosseus (FDI), orbicularis oculi (o. oculi) and mentalis muscles. Result: TMS evoked MEPs in o. oculi on both ipsi- and contralateral sides in all subjects. In the paired-pulse study, MEP amplitude in the mentalis decreased at short ISIs of 1-3 ms, followed by increases at 12-20 ms. These effects were similar to those in the FDI. O. oculi did not show a distinct inhibitory period at short ISIs and facilitation at long ISIs was detected but was significantly less than in FDI and mentalis. In o. oculi, there was no significant difference between the effects of ipsilateral and contralateral CS on the MEPs. Conclusion: The bi-hemispheric control of volitional movement and the modulation from brainstem projections appear to markedly influence intracortical inhibitory and excitatory systems in the motor cortical representation of o. oculi. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

The effects of different phases of an observed movement on the modulation of cortical motor output were studied by means of transcranial magnetic stimulation (TMS). A video-clip of a reaching-grasping action was shown and single TMS pulses were delivered during its passive observation, Times of cortical stimulation were related to the phases of the shown movement, locking them to the appearance of specific kinematic landmarks. The amplitude of the motor evoked potentials (MEPs) induced by TMS in the first dorsal interosseus (FDI) muscle was modulated by the amount of the observed finger aperture. The presence of such an effect is consistent with the notion of a mirror neuron system in premotor areas that couples action execution and action observation also in terms of temporal coding. © 2001 Lippincott Williams & Wilkins.

This kinematic study aimed to determine whether color is a stimulus property involved in the control of reaching-grasping movements. Subjects reached and grasped a target-object, located either on the right or on the left of the subject's midline. A distractor, placed along the subject's midline, could be randomly presented. The colors, i.e., both chromaticity (red and green stimuli were presented) and lightness, of the target and distractor were varied in experiment 1. Only stimulus lightness and only stimulus chromaticity were varied in experiments 2 and 3, respectively. In experiment 4 subjects matched with their thumb and index finger the size of the target-stimuli presented in experiment 1. Chromaticity (experiments 1 and 3) of the target and distractor influenced grasp, but not reach. Maximal finger aperture was larger during grasping the red than the green target. Data collected in the matching task (experiment 4) confirmed a trend to overestimate the red target and to underestimate the green one. During grasp, hand shaping was influenced by distractor chromaticity when it was different from target chromaticity. Distractor lightness affected reach, but not grasp (experiments 1 and 2). Reach was slower when the distractor was lighter and arm trajectory veered away from it. The results of the present study suggest that color, that is the ensemble of chromaticity and lightness, is a stimulus property involved in the control of reaching-grasping. The different effects of target color on reach and grasp support the notion that intrinsic object properties, such as color, affect grasp more than reach. In addition, the different effects of distractor chromaticity and lightness on reach and grasp confirm that target-objects are visually extracted from surrounding cues by means of different processes, according to the required motor response. © Springer-Verlag 2001.

The aim of the present study was to determine whether children like adults (Gentilucci M, Chieffi S, Daprati E, Saetti MC, Toni I. Visual illusion and action. Neuropsychologia 1996;34:369-76; Gentilucci M, Daprati E, Gangitano M, Toni I. Eye position tunes the contribution of allocentric and egocentric information to target localisation in human goal directed arm movements. Neurosci Lett 1997;222:123-6) are influenced by visual illusions when they transform visual information in motor command. Children and adults pointed to a shaft extremity of the Müller-Lyer configurations, as well as to an extremity of a control configuration. Movements were executed in two experimental conditions. In the vision condition subjects saw both the stimulus and their hand before and during movement. In the no vision (memory) condition subjects saw the stimulus and their hand before, but not during movement. Movement started 5 s after vision was precluded. The Müller-Lyer illusion affected pointing kinematics of both children and adults. As found previously (Gentilucci M, Chieffi S, Daprati E, Saetti MC, Toni I. Visual illusion and action. Neuropsychologia 1996;34:369-76; Gentilucci M, Daprati E, Gangitano M, Toni I. Eye position tunes the contribution of allocentric and egocentric information to target localisation in human goal directed arm movements. Neurosci Lett 1997;222:123-6), subjects undershot and overshot the shaft extremity of the closed and of the open configuration, respectively. The illusion effect was greater in the no vision than in the vision condition. These results show that in children like in adults the system underlying visual perception in an object-centered frame of reference and that involved in motor control functionally interact with each other. Although the processes of target localisation were the same, the transformation of target position information in a sequence of motor patterns was different in children from that in adults. Even if both children and adults lengthened duration of the deceleration phase in the vision condition, only adults shortened duration of the acceleration phase in order to maintain constant movement time (Viviani P, Schneider R. A developmental study of the relationship between geometry and kinematics in drawing movements. J Exp Psychol 1991;17:198-218). This result suggests that children are yet unable to co-ordinate temporally acceleration with deceleration phase. © 2001 Elsevier Science Ltd.

Selective deficits in producing verbs relative to nouns in speech are well documented in neuropsychology and have been associated with left hemisphere frontal cortical lesions resulting from stroke and other neurological disorders. The basis for these impairments is unresolved: Do they arise because of differences in the way grammatical categories of words are organized in the brain, or because of differences in the neural representation of actions and objects? We used repetitive transcranial magnetic stimulation (rTMS) to suppress the excitability of a portion of left prefrontal cortex and to assess its role in producing nouns and verbs. In one experiment subjects generated real words; in a second, they produced pseudowords as nouns or verbs. In both experiments, response latencies increased for verbs but were unaffected for nouns following rTMS. These results demonstrate that grammatical categories have a neuroanatomical basis and that the left prefrontal cortex is selectively engaged in processing verbs as grammatical objects.

Neurons involved in grasp preparation with hand and mouth were previously recorded in the premotor cortex of monkey. The aim of the present kinematic study was to determine whether a unique planning underlies the act of grasping with hand and mouth in humans as well. In a set of four experiments, healthy subjects reached and grasped with the hand an object of different size while opening the mouth ( experiments 1 and 3), or extending the other forearm ( experiment 4), or the fingers of the other hand ( experiment 5). In a subsequent set of three experiments, subjects grasped an object of different size with the mouth, while opening the fingers of the right hand ( experiments 6–8). The initial kinematics of mouth and finger opening, but not of forearm extension, was affected by the size of the grasped object congruently with the size effect on initial grasp kinematics. This effect was due neither to visual presentation of the object, without the successive grasp motor act ( experiment 2) nor to synchronism between finger and mouth opening ( experiments 3, 7, and 8). In experiment 9 subjects grasped with the right hand an object of different size while pronouncing a syllable printed on the target. Mouth opening and sound production were affected by the grasped object size. The results of the present study are discussed according to the notion that in an action each motor act is prepared before the beginning of the motor sequence. Double grasp preparation can be used for successive motor acts on the same object as, for example, grasping food with the hand and ingesting it after bringing it to the mouth. We speculate that the circuits involved in double grasp preparation might have been the neural substrate where hand motor patterns used as primitive communication signs were transferred to mouth articulation system. This is in accordance with the hypothesis that Broca's area derives phylogenetically from the monkey premotor area where hand movements are controlled.

We investigated the possible influence of automatic word reading on processes of visuo-motor transformation. Subjects reached and grasped an object on which the following Italian words were printed: 'VICINO' (near) or 'LONTAN' (far) on an object either near or far from the agent (experiments 1, 2); PICCOLO (small) or 'GRANDE' (large) on either a small or a large object (experiment 4); and 'ALTO' (high) or 'BASSO' (low) on either a high or a low object (experiment 5). The kinematics of the initial phase of reaching-grasping was affected by the meaning of the printed words. Namely, subjects automatically associated the meaning of the word with the corresponding property of the object and activated a reach and/or a grasp motor program influenced by the word. No effect on initial reach kinematics was observed for words related to object properties not directly involved in reach control (experiment 3). Moreover, in all the experiments, the presented words poorly influenced perceptual judgement of object properties. In experiments 5-7, the effects of the Italian adjectives 'ALTO' (high) and 'BASSO' (low) on reaching-grasping control were compared with those of the Italian adverbs 'SOPRA' (up) and 'SOTTO' (down). Adjectives influenced visual analysis of target-object properties, whereas adverbs more directly influenced the control of the action. We suggest that these effects resemble the structure of a sentence, where adjectives are commonly referred to nouns, and adverbs to verbs. In other words, class of words and, in a broad sense, grammar influenced motor control. The results of the present study show that cognitive functions such as language can affect visuo-motor transformation. They are discussed according to the notion that a strict relation between language and motor control exists, and that the frontal cortex can be involved in interactions between automatic word reading and visuo-motor transformation.

The present study aimed to demonstrate that motor representations are used to recognise biological stimuli. In three experiments subjects were required to judge laterality of hands and forearms presented by pictures. The postures of the hands were those assumed when holding a small, medium and large sphere. In experiment 1, the sphere held in hand was presented, whereas in experiment 2 it was absent. In experiment 3, the same images, showing holding-a-sphere hands, as in experiment 1 were presented, but without forearm. In all experiments one finger of each hand could be absent. In experiment 1 recognition time was longer for those hand postures for which the corresponding grasping motor acts required more accuracy. This was confirmed by a control experiment (experiment 4), in which subjects actually grasped the spheres. Absence of fingers did not influence right-left hand recognition. However, the absence of target object in experiment 2, and of forearm in experiment 3 reduced the effects of the type of holding on hand laterality recognition. The results of the present study indicate that grasp representations are used to recognise hand laterality. In particular, the visual description of how hand and object interact in space (the opposition space [M.A. Arbib, Programs, schemas and neural networks for control of hand movement: beyond the RS frameworks, in: M. Jeannerod (Ed.), Attention and Performance XIII: Motor Representation and Control, Lawrence Erlbaum, Hillsdale, NJ, 1990, 111-138; M.A. Arbib, T. Iberall, D. Lyons, Coordinated control programs for movements of the hand, in: A.W. Goodman, I. Darian-Smith (Eds.), Hand function and the neocortex, Springer, Berlin, 1985, pp. 135-170]) and the anchoring of the hand to the agent are the features of the grasp representations used in hand-recognition processes. The data are discussed according to the more general notion that motor representations are automatically extracted in the process of intuiting situations, or people's intentions. These motor representations, which are compared with those of other people, contain concrete information on the actions (the motor program) by which a situation is created and on the aim of the agents executing those actions. © 2000 Elsevier Science B.V.

The kinematics of the action formed by reaching-grasping an object and placing it on a second target was studied in a patient who suffered from an acute vascular left brain lesion, which affected the Supplementary Motor Area proper (SMA-proper) (Matelli M, Luppino G. Thalamic input to mesial and superior area 6 in the macaque monkey. Journal of Comparative Neurology 1996;372:59-87, Matelli M, Luppino G, Fogassi L, Rizzolatti G. Thalamic input to inferior area 6 and area 4 in the macaque monkey. Journal of Comparative Neurology 1989;280:468-488), and in five healthy control subjects. The reach kinematics of the controls was affected by the positions of both the reaching-grasping and the placing targets (Gentilucci M, Negrotti A, Gangitano M. Planning an action. Experimental Brain Research 1997;115:116- 28). In contrast, the reach kinematics of the patient was affected only by the position of the reaching-grasping target. By comparing these results with those previously found in Parkinson's disease patients executing the same action (Gentilucci M, Negrotti A. Planning and executing an action in Parkinson's disease patients. Movement Disorders 1999;1:69-79, Gentilucci M, Negrotti A. The control of an action in Parkinson's disease. Experimental Brain Research 1999;129:269-277), we suggest that the anatomical 'motor' circuit formed by SMA-proper (see above), Basal Ganglia (BG) and Thalamus (Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends in the Neurosciences 1990;13:266-271, Hoover JE, Strick PL. Multiple output channels in the basal ganglia. Nature 1993;259:819-821) may be involved in the control of actions: SMA-proper assembles the sequence of the action, whereas BG updates its parameters and stores them. (C) 2000 Elsevier Science Ltd.

In the present study, we addressed the problem of whether hand representations, derived from the control of hand gesture, are used in handedness recognition. Pictures of hands and fingers, assuming either common or uncommon postures, were presented to right-handed subjects, who were required to judge their handedness. In agreement with previous results (Parsons, 1987, 1994; Gentilucci, Daprati, & Gangitano, 1998), subjects recognized handedness through mental movement of their own hand in order to match the posture of the presented hand. This was proved by a control experiment of physical matching. The new finding was that presentation of common finger postures affected responses differently from presentation of less common finger postures. These effects could be not attributed to mental matching movements nor related to richness in hand-finger cues useful for handedness recognition. The results of the present study are discussed in the context of the notion that implicit visual analysis of the presented hands is performed before mental movement of one's hand takes place (Parsons, 1987; Gentilucci et al., 1998). In this process, hand representation acquired by experience in the control and observation of one's and other people's hand gestures is used. We propose that such an immediate recognition mechanism belongs to the class of mental processes which are grouped under the name of intuition, that is, the processes by which situations or people's intentions are immediately understood, without conscious reasoning. © 1998 Academic Press.

We investigated the possible influence of automatic word reading on processes of visuo-motor transformation. Six subjects were required to reach and grasp a rod on whose visible face the word 'long' or 'short' was printed. Word reading was not explicitly required. In order to induce subjects to visually analyse the object trial by trial, object position and size were randomly varied during the experimental session. The kinematics of the reaching component was affected by word presentation. Peak acceleration, peak velocity, and peak deceleration of arm were higher for the word 'long' with respect to the word 'short'. That is, during the initial movement phase subjects automatically associated the meaning of the word with the distance to be covered and activated a motor program for a farther and/or nearer object position. During the final movement phase, subjects modified the braking forces (deceleration) in order to correct the initial error. No effect of the words on the grasp component was observed. These results suggest a possible influence of cognitive functions on motor control and seem to contrast with the notion that the analyses executed in the ventral and dorsal cortical visual streams are different and independent.

We used an interference paradigm in order to study integration between haptic and visual information in motor control and in perceptual analysis. Subjects either reached and grasped a visually presented sphere or matched its size with their left hand while manipulating with their right hand another sphere whose size could be smaller or greater. In four experiments haptic analysis of the manipulated sphere could be either automatically incorporated with or explicitly dissociated from visual analysis. In a fifth experiment reaching-grasping and matching were executed with the right hand, whereas manipulation was executed with the left hand. Manipulation with the right hand influenced finger shaping during grasping with the left hand when the sizes of the two objects were different. Interference was observed mainly in those experiments in which haptic analysis could be automatically integrated with visual analysis. In the matching task, no effect was observed. Finally, manipulation with the left hand did not produce any interference effect on reaching-grasping and matching executed by the right hand. The results of the present study suggest that somesthetic information is integrated with visual information only in sensorimotor transformations. In addition, they support the notion that the left hemisphere together with the right hemisphere is involved in the control of left hand reaching- grasping movements.

The visual control of our own hand when dealing with an object and the observation of interactions between other people's hand and objects can be involved in the construction of internal representations of our own hand, as well as in hand recognition processes. Therefore, a different effect on handedness recognition is expected when subjects are presented with hands holding objects with either a congruent or an incongruent type of grip. Such an experiment was carried out on right-handed and left-handed subjects. We expected that the different degree of lateralisation in motor activities observed in the two populations [J. Herron, Neuropsychology of left- handedness, Academic Press, New York, 1980.] could account for the construction of different internal hand representations. As previously found [L.M. Parsons, Imaged spatial transformations of one's hands and feet, Cogn. Psychol., 19 (1987) 178-241.], in order to identify handedness, subjects mentally rotated their own hand until it matched with the presented one. This process was confirmatory, being preceded by an implicit visual analysis of the target hand. Presentation of hands holding objects with congruent or incongruent types of grip influenced handedness recognition at different stages in right-handed and left-handed subjects. That is, the mental rotation stage was affected in right-handed subjects, whereas the initial phase of implicit hand analysis was affected in left-handed subjects. We suggest that in handedness recognition, left-handers relied more on a pictorial hand representation, whereas right-handers relied more on a pragmatic hand representation, probably derived from experience in the control of their own movements. The use of different hand representations may be due to differential activation of temporal and premotor areas.

In the present study we addressed the issue of how an object is visually isolated from surrounding cues when a reaching-grasping (prehension) movement towards it is planned. Subjects were required to reach and grasp an object presented either alone or with a distractor. In five experiments, different degrees of elaboration of the distractor were induced by varying: (1) the position of the distractor (central or peripheral); (2) the time when the distractor was suppressed (immediately or delayed, with respect to stimulus presentation); and (3) the type of distractor analysis (implicit or explicit). In addition, we tested whether the possible effects of the distractor on reaching-grasping were due to the use of an allocentric reference centered on it. This was obtained by comparing the effects of the distractor with those of a stimulus, the target of a placing movement successive to the reaching-grasping. The results of the five experiments can be summarized as follows. The necessary condition for an interference effect on both the reaching and the grasping components was the central presentation of the distractor. When the information on the distractor could be immediately suppressed, an interference effect was observed only on the grasp component. In the case of delayed suppression, an effect was found on the reaching component. Finally, when an overt analysis of the distractor was required, the interference effect disappeared. Two main conclusions have been drawn from the results of the present study. First, comparison between properties of the target and surrounding cues is performed by two independent processes for reaching and grasping an object. The process for the grasp relies more on allocentric cues than that for the reach. Second, when surrounding stimuli are automatically analyzed during visual search of the target, the process of visuo-motor transformation can incorporate their features into the target. In contrast, overt analysis of surrounding stimuli is performed separately from that of the target. Finally, the data of the present study are discussed in support of the premotor theory of attention.

The motor control of a sequence of two motor acts forming an action was studied in the present experiment. The two analysed motor acts were reaching-grasping an object (first target) and placing it on a second target of the same shape and size (experiment 1). The aim was to determine whether extrinsic properties of the second target (i.e. target distance) could selectively influence the kinematics of reaching and grasping. Distance, position and size of both targets were randomly varied across the experimental session. The kinematics of the initial phase of the first motor act, that is, velocity of reaching and hand shaping of grasping, were influenced by distance of the second target. No kinematic difference was found between movements executed with and without visual control of both hand and targets. These results could be due to computation of the general program of an action that takes into account extrinsic properties of the final target. Conversely, they could depend on a visual interference effect produced by the near second target on the control of the first motor act. In order to dissociate the effects due to second target distance from those due to visual interference, two control experiments were carried out. In the first control experiment (experiment 2) subjects executed movements directed towards spatial locations at different distances from the first target, as in experiment 1. However, the near second target was not presented and subjects were required to place the object on an arbitrary near position. Distance of the second (either real or arbitrary) target affected the reaching component of the first motor act, as in experiment 1, but not the grasp component. In the second control experiment (experiment 3), the pure visual interference effect was tested. Subjects were required to reach and grasp the object and to lift it in either presence or absence of a second near stimulus. No effect on the initial phase of the first motor act was observed. The results of the this study suggest a dissociation in the control of reaching and grasping, concerning not only visual analysis of extrinsic properties of the immediate target but also visual analysis of the final target of the action. In other words, the notion of modularity for the motor control can be extended to the construction of an entire action.

Subjects were required to point to the distant vertex of the closed and the open configurations of the Muller-Lyer illusion using either their right hand (experiment 1) or their left hand (experiment 2). In both experiments the Muller-Lyer figures were horizontally presented either in the left or in the right hemispace and movements were executed using either foveal or peripheral vision of the target. According to the illusion effect, subjects undershot and overshot the vertex location of the closed and the open configuration, respectively. The illusion effect decreased when the target was fixated and when the stimulus was positioned in the right hemispace. These results confirm the hypothesis that both egocentric and allocentric information are combined in order to encode target position in space. When movements are directed to foveal targets, decreasing effects of allocentric cues, as shown by decreasing the illusion effect, could be due to enhanced efficiency of the egocentric system. That is, information on eye position when target is fixated can be used to precisely establish its spatial relations with the body. In addition, a more accurate analysis of allocentric information is hypothesized when the target is positioned in the left hemispace. In other words, our data confirm the notion that the right cerebral hemisphere is involved in space representation.

Many experimental evidences highlighted that Parkinson Disease (PD) patients are particularly impaired in performing a sequence of movements. In the present experiment we focused to study how PD patients plan and execute an action constituted by the sequence of reaching-grasping an object (first motor act) and placing it on a second target (second motor act). We wished to determine whether properties of the target of the second motor act influenced the kinematics of first motor act. The results showed that PD patients modified, as the controls, the initial ballistic phase of reaching according to variation of second target position (object extrinsic properties). In particular, peak acceleration was higher for farther position of the second target. However, in the subsequent phase the patients, differently from the controls, modified their reaching kinematics removing the effects of second target distance. In other words the patients re-programmed the reaching component by taking into account only properties of the first target. This effect was obtained by varying the duration of the acceleration phase. These results indicate that PD patients are able to compute the general program of an action that takes into account extrinsic properties of the final target. However, this program decays during its execution inducing premotor areas to reprogram it. This finding provides a further evidence of the role of the basal ganglia as structure involved in the storing motor program and in controlling the action.

Subjects were required to reach and grasp a parallelepiped, the position, orientation and size of which were varied. The kinematics of reaching and grasping movements was studied in full vision and in no vision conditions. Both direction and movement amplitude of reaching were affected by object orientation. Conversely, both the time course of finger axis orientation and the angular displacement of the hand at wrist were influenced by object position. These results were not modified by the absence of visual control. Finger aperture during grasping was affected by both object size and orientation. This latter result was not due to a distorted size perception, as shown by a control matching experiment. Taken together, the results of the present study suggest the integration between distal and proximal components during reaching and grasping.