Maria Giuseppina Palmieri

Influence of the supplementary motor area on primary motor cortex excitability during movements triggered by neutral or emotionally unpleasant visual cues

The stronger anatomo-functional connections of the supplementary motor area (SMA), as compared with premotor area (PM), with regions of the limbic system, suggest that SMA could play a role in the control of movements triggered by visual stimuli with emotional content. We addressed this issue by analysing the modifications of the excitability of the primary motor area (M1) in a group of seven healthy subjects, studied with transcranial magnetic stimulation (TMS), after conditioning TMS of SMA, during emotional and non-emotional visually cued movements. Conditioning TMS of the PM or of contralateral primary motor cortex (cM1) were tested as control conditions. Single-pulse TMS over the left M1 was randomly intermingled with paired TMS, in which a conditioning stimulation of the left SMA, left PM or right M1 preceded test stimulation over the left M1. The subjects carried out movements in response to computerised visual cues (neutral pictures and pictures with negative emotional content). The amplitudes of motor-evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle after paired TMS were measured and compared with those obtained after single-pulse TMS of the left M1 under the various experimental conditions. Conditioning TMS of the SMA in the paired-pulse paradigm selectively enhanced MEP amplitudes in the visual-emotional triggered movement condition, compared with single-pulse TMS of M1 alone or with paired TMS during presentation of neutral visual cues. On the other hand, conditioning TMS of the PM or cM1 did not differentially influence MEP amplitudes under visual-emotional triggered movement conditions. This pattern of effects was related to the intensity of the conditioning TMS over the SMA, being most evident with intensities ranging from 110% to 80% of motor threshold. These results suggest that the SMA in humans could interface the limbic and the motor systems in the transformation of emotional experiences into motor actions.

Neurophysiological follow-up of motor cortical output in stroke patients

BACKGROUND AND PURPOSE Transcranial magnetic stimulation (TMS) has been employed in following up a population of 20 stroke patients in a post-acute, apparently stabilized stage. Neurophysiological and clinical data were recorded in 5 different recording sessions, from the beginning of a neuro-rehabilitation treatment (T0, at about 5 weeks from the ictal event.), followed up for about 4 months (T4), with the purpose to study any modification of the cortical motor output in the course of a neuro-rehabilitation treatment. METHODS Motor evoked potentials (MEPs) were simultaneously recorded from 10 muscles of both upper limbs (affected and not-affected); meanwhile, clinical and functional scores were gathered. Spinal responsiveness was investigated via H-reflex and F-wave recordings. RESULTS We describe a pattern of improving changes still taking place four months after the stroke, even if the maximal amelioration burden was concentrated between T0 and T1 and T1 and T2 recording sessions (T0/admission to T2/42 days from T0=about 80 days from stroke occurrence). In particular, the excitability threshold (ETh) was progressively decreasing in the affected hemisphere (AH; P<0.001 between T0 and T4), while MEPs amplitude and latency tended toward normality, more in the resting state than during voluntary contraction. Slopes of neurophysiological and clinical data evolution were taken and trends of amelioration described. CONCLUSIONS These findings suggest that rearrangements of motor cortical neural circuitries are still operating after several months from an acute vascular monohemispheric insult, coupled with a clinical improvement in disability and neurological scores. The steepest part of the slopes were evident in the first 80 days, suggesting that this period is the one in which plastic changes of cortical motor areas are mainly active.

Distinguishing forms of generalized epilepsy using magnetic brain stimulation

In this study, we have used paired transcranial stimulation of the motor cortex to test the hypothesis that cortical inhibition is decreased in juvenile myoclonic epilepsy (JME). The double shock technique was adopted here because it offers a means for highlighting abnormal inhibitory mechanisms. From previous experiments performed on healthy subjects, it is known that a magnetic conditioning stimulus, of subthreshold intensity, suppresses the MEP in response to a subsequent suprathreshold stimulus delivered after 1-4 msec. JME patients were selected as a potential contrast with other forms of idiopathic generalized epilepsy, because they complain of myoclonic jerks without loss of consciousness, indicating with certainty a dysfunction of the motor cortex. Two patients with sporadic grand mal and one non-epileptic patient were also investigated. Paired stimulation was produced by a Bi-stim (Magstim) stimulator, with a figure-of-8 coil placed over the hand area of the motor cortex, and a set of interstimulus intervals (ISIs) ranging from 1 to 6 msec was analyzed. In JME patients there were two indications of abnormality with respect to normal subjects and to the other epileptic patients: (1) the absence of MEP suppression to paired stimulation; (2) a progressive amplitude increase of MEPs to the test stimulus alone. In the two patients with the other form of epilepsy the pattern of inhibition was broadly preserved, even though there was some difference from the normal profile. The results suggest that the loss of MEP inhibition can be regarded as a marker of JME.

Different TMS patterns of intracortical inhibition in early onset Alzheimer dementia and frontotemporal dementia.

OBJECTIVE To investigate putative changes in cortical excitability of patients affected by early-onset mild dementia by means of transcranial magnetic stimulation (TMS) and to verify whether a peculiar neurophysiological profile may contribute to characterise Alzheimers disease (AD) vs frontotemporal dementia (FTD). METHODS Motor threshold and intracortical inhibition (ICI) and facilitation (ICF) after paired-pulse TMS (inter-stimulus intervals from 1 to 20 ms) were studied in two groups of early-onset demented patients with a neuropsychological profile suggestive of AD (n = 12) and FTD (n = 8). Twelve age-matched healthy subjects were considered as control group. In both patient groups, recordings were performed before and after a single oral dose of 4 mg galantamine. RESULTS No significant difference in motor threshold was observed among the three studied groups. On the contrary, early-onset AD showed a significant reduction of ICI compared to control group, no changes were detected in FTD patients. No significant changes in ICF were found between both patient groups and healthy subjects. The acute administration of galantamine reversed the modified ICI in AD group. CONCLUSIONS The differential pattern of ICI exhibited by early-onset AD vs FTD in the early stage of disease may represent a non-invasive, reproducible electrophysiological tool, which may contribute to early differential diagnosis and, possibly, to monitor therapeutic effectiveness. SIGNIFICANCE The present results support the possibility that subtle, early modifications in intracortical circuitry features AD, but not FTD patients.

Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson's disease paralleling apomorphine effects: a paired magnetic stimulation study

OBJECTIVE We investigated the effect of bilateral subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on intracortical inhibition (ICI) in patients with advanced Parkinsons disease (PD). METHODS The activity of intracortical inhibitory circuits was studied in 4 PD patients implanted with stimulating electrodes both in STN and GPi by means of paired-pulse transcranial magnetic stimulation, delivered in a conditioning-test design at short (1-6 ms) interstimulus intervals (ISI). The effect of apomorphine on the same PD patients was also investigated. RESULTS We observed that implanted PD patients showed a significant increase in ICI during either bilateral STN or GPi DBS at 3 ms ISI, and during bilateral STN DBS at 2 ms ISI in comparison to their off DBS condition. The same statistical improvement was observed during apomorphine infusion at 3 and 2 ms ISI. In each condition, the electrophysiological changes were associated with a significant clinical improvement as measured by the Unified Parkinsons Disease Rating Scale motor examination. CONCLUSIONS These results are consistent with the hypothesis that basal ganglia DBS can mimic the effects of pharmacological dopaminergic therapy on PD patients cortical activity. We propose that in PD patients, the basal ganglia DBS-induced improvement of ICI may be related to a recovery in modulation of thalamo-cortical motor pathway.

Pharmacologic reversal of cortical hyperexcitability in patients with ALS

Objective: To reverse the profile of abnormal intracortical excitability in patients with ALS by administering drugs that promote GABAergic transmission. Background: Transcranial magnetic stimulation (TMS) has revealed abnormalities of cortical inhibition in ALS, a reduction of the silent period, and the absence of intracortical inhibition normally occurring in response to paired TMS. Impaired inhibitory transmission could play a role in the physiopathology of this illness. Methods: Using paired TMS with conditioning stimuli from 1-to-6-msec-interstimulus intervals, we investigated 16 patients with ALS. The protocol included: (1) the “drug-free” profile of paired TMS; (2) paired TMS 30 minutes after the intake of diazepam (3.5 mg); (3) paired TMS after 3 weeks’ treatment with gabapentin (GBP) (600 mg/day) or riluzole (50 mg/twice a day). Results: Intracortical inhibition is lost in patients with ALS, and this abnormal profile is reversed by diazepam or sustained treatment with GBP. We also noted that motor-evoked potential amplitudes to single stimuli increased (p < 0.01) after diazepam and GBP. Conclusions: The demonstration of pharmacologic reversal of hyperexcitability in patients with ALS makes a potentially significant contribution toward understanding the pathophysiology of a disease that has so far eluded an effective cure.

Ipsilateral motor activation in patients with cerebral gliomas

Objective: The aim of this study is to provide neurophysiologic evidence of ipsilateral hemispheric activation in patients affected by intracerebral gliomas via the use of transcranial magnetic stimulation. Background: The mechanisms involved in such ipsilateral activation have yet to be established, but they may involve preexisting routes that either are suppressed or undetected in the normal brain. Ipsilateral pathways may act in reserve, activated by the impairment of contralateral control. This hypothesis is suggested by the fact that the considerable size of the tumors in our patients is not matched by a proportionate loss of motor performance in the limbs contralateral to the affected hemisphere. However, it remains possible that ipsilateral motor-evoked potentials (iMEPs) may reflect reorganizational changes without significant functional effects. Methods: The effects of such activation were investigated using both focal and nonfocal coils stimulating cortical motor areas, with MEPs recorded from both left and right thenar muscles. Fifteen healthy control subjects and seven patients were examined. Results: iMEPs were generally absent in normal subjects, but in contrast they were obtained in the patients by stimulating the healthy hemisphere using both round and figure-of-eight coils. Distinct from contralateral MEPs, iMEPs are obtained with higher thresholds (range, 60 to 80% of stimulator output) and display longer latencies (20.9 msec versus 19.4 msec). Conclusions: Taken in conjunction with recent research using functional imaging brain exploration and a variety of clinical, anatomic, and neurophysiologic studies, our results reflect a growing awareness of ipsilateral motor control and its potential compensatory role when contralateral routes are damaged.

Effect of Vigabatrin on motor responses to transcranial magnetic stimulation: An effective tool to investigate in vivo GABAergic cortical inhibition in humans

In this study, transcranial magnetic stimulation (TMS) of the hand primary motor area was used to test possible excitability changes induced by the administration of Vigabatrin (Gamma-Vinyl-gamma-aminobutryic acid;4-amino-hex-5-enoic acid; GVG), a selective GABAergic drug, on cortical inhibitory mechanisms in healthy subjects. In a group of 15 healthy volunteers, the level of motor cortical excitability was studied by means of paired-pulse TMS (p-TMS) protocols exploring the early (1-6 ms of interstimulus intervals, ISI) and the late cortical inhibition (20-250 ms ISI), and by evaluating the cortical silent period (CSP) duration obtained in response to single pulse stimulation of cortical motor area. In all participants TMS procedures were carried out before and after administering GVG for three consecutive days at a daily dosage of 50 mg/kg. Three months later, a third TMS recording session was repeated to investigate possible long-lasting GVG effects on cortical excitability. GVG induces relevant changes of cortical excitability consisting in an increase of late cortical inhibition in response to the long ISI p-TMS and in a prolonged duration of the CSP. No significant change in the early cortical inhibition was observed in response to the short ISI p-TMS. The analysis of peripheral motor excitability was also assessed, with no effects. The present electrophysiological data show that GVG is able to induce a significant increase of the late cortical inhibition, whereas it does not affect the early cortical inhibition. These data suggest that the great availability of synaptic GABA differently acts on the inhibitory circuitries controlled by different GABA-receptor subtypes.

Effects of motor imagery on motor cortical output topography in Parkinson’s disease

Background: The motor impairment in Parkinson’s disease (PD) could partly reflect a failure to activate processes of motor imagery. Objective: To verify any selective changes of motor output during motor imagery, lateralized to the hemisphere contralateral to the clinically affected side of hemiparkinsonian patients. Methods: Transcranial magnetic stimulation (TMS) was used to map the cortical representations of the contralateral abductor digiti minimi muscle (ADM) during rest, contraction, and motor imagery in a group of patients with hemi-PD and in a group of healthy volunteers. Seven patients with hemi-PD and seven healthy subjects were examined. Focal TMS was applied over a grid of 20 scalp positions on each hemiscalp. Maps were characterized by area (number of excitable positions), volume (the sum of motor evoked potential amplitudes at all scalp positions), and center of gravity (a map position representing an amplitude-weighted calculation of the excitable area). Results: In healthy control subjects, the area of cortical representation of ADM was symmetrically increased in both hemispheres by mental simulation of movement and real muscle contraction. In patients with hemi-PD, there was a hemispheric asymmetry in the area of cortical representation elicited by motor imagery. The area was reduced in the clinically affected hemisphere. The volume of cortical representation was increased under all conditions and in both hemispheres in patients with PD. However, largely because the volume was so high at rest in patients, the increment in volume associated with contraction was smaller than in control subjects. Conclusion: This study demonstrates the presence of a tonic hyperactivation of motor cortical circuitry in PD in conjunction with an abnormality of either motor imagery or the process by which motor imagery engages the sensorimotor cortices in the clinically affected hemisphere.

Effect of paired transcranial magnetic stimulation on the cortical silent period.

OBJECTIVE To investigate the behaviour of silent period (SP) during paired magnetic cortical stimulation. BACKGROUND Paired cortical magnetic stimulation is known to inhibit or facilitate motor evoked potentials (MEPs), but no attention has been paid to its effect on SP. METHODS SP was measured in the contracted first dorsal interosseus muscle after paired cortical stimuli at given interstimulus intervals (ISIs) in eight healthy subjects. Test stimulus intensity was fixed at 110% of resting threshold (RT), while three levels of conditioning stimulus intensities at 40%, 65% and 90% RT were separately employed. We also examined the effect of progressively increasing the test stimulus intensity (120-150 RT) on SP while maintaining stable conditioning stimulus intensity. RESULTS 65% RT conditioning stimulus shortened the SP at 1-3 ms ISIs with MEP size reduction, and prolonged the SP at 15-20 ms ISIs without affecting MEP size. 90% RT conditioning stimulus showed only SP prolongation, while 40% RT showed only SP shortening at 1 ms ISI. The SP shortening at 2 ms ISI was the most evident with 120% RT test stimulus, but without correlation with the MEP size. The SP prolongation at 15 ms ISI was maximal with 110% RT test stimulus and then almost abolished with 150% RT. The SP shortening at short intervals might be due not only to spinal but also to suprasegmental mechanisms, conceivably mediating cortical excitatory drive to the corticospinal tract. The SP prolongation at intermediate intervals might be due to activation of slowly conducting, intra- or sub-cortical polysynaptic pathways exerting a facilitatory drive on the cortical inhibitory interneurons.