Differential Influence of Carotid Stenosis and White Matter Disease on Motor and Cognitive Activation.

BACKGROUND: Cognitive and motor performance can be supported, especially in older subjects, by different types of brain activations, which can be accurately studied by functional magnetic resonance imaging (fMRI). Vascular risk factors (VRFs) are extremely important in the development of cognitive impairment, but few studies have focused on the fMRI cortical activation characteristics of healthy subjects with and without silent cerebrovascular disease including white matter hyperintensities (WMH) and carotid stenosis (CS) performing cognitive tasks. METHODS: Thirty-five volunteers with and without asymptomatic unilateral carotid stenosis above 70% and variable degrees of WMH underwent performance of a simple motor and cognitive task during an fMRI session. RESULTS: While the performance of the motor task resulted in a cortical activation dependent of age but not of WMH and carotid stenosis, performance of the cognitive task was accompanied by a significantly increased activation independently correlated with age, presence of WMH as well as of carotid stenosis. CONCLUSIONS: in this study, cognitive domains regulating attention and working memory appear to be activated with a pattern influenced by the presence of carotid stenosis as well as by white matter hyperintensities. The impairment of these cognitive abilities is of high relevance in Alzheimer's disease pathology. The fMRI pattern shown in patients with asymptomatic but significant carotid stenosis might be related to chronic cerebrovascular hypoperfusion, a critical pathophysiological mechanisms in AD. In these patients, carotid endoarterectomy should be considered also for AD prevention and might be recommended.

CSF from MS patients can induce acute conduction block in the isolated optic nerve.

In the present in vitro electrophysiological study, the acute effects of the cerebrospinal fluid (CSF) from multiple sclerosis (MS) and control subjects were measured on the axonal conduction of rat optic nerve, a central tract that is commonly affected in MS. Optic nerve compound action potential (CAP) amplitude was insensitive to the application of CSF obtained from the whole population of non-MS patients and from seven of 15 MS CSF. In the remaining eight MS cases, conversely, a time-dependent depression of CAP amplitude was observed. The reversible blockade of ion channels by soluble substances might account, at least in part, for the transient symptoms often seen in MS patients.

Pramipexole in comparison to l-dopa: a neuropsychological study.

Twenty right-handed patients affected by early/mild Parkinson's disease were evaluated in a randomised study using neuropsychological and clinical assessements during three treatment modalities: when in the off treatment condition, when on pramipexole, and when on l-dopa. In comparison to the off treatment condition, the DA-agonist pramipexole produced a significant impairment of short term verbal memory, attentional-executive functions and verbal fluency, while l-dopa did not. Moreover, pramipexole opposite to l-dopa, failed to improve FAS and Stroop tests. Present findings indicate that pramipexole may worsen cognitive functions although not exceeding normative values.

Ipsilateral activation of the unaffected motor cortex in patients with hemiparetic stroke.

BACKGROUND AND PURPOSE: Recent research has shown that following stroke patients can display ipsilateral activity reflecting a functional link between the undamaged hemisphere and the affected upper limb on the same side of the body. In the present study the capacity for ipsilateral activation is documented during recovery by using transcranial magnetic stimulation (TMS) and transcranial Doppler (TCD). METHODS: Fourteen patients affected by hemispheric stroke were examined with TMS and TCD within 48 h of onset, and again 6 months later. Neurological signs were scored with reference to the NIHSS, and patients executed a thumb to finger opposition task so as to further estimate the motor deficit. Twenty healthy volunteers represented the control population. RESULTS: (1) Both TMS and TCD yielded homogeneous results showing ipsilateral activity between affected hands and undamaged hemispheres. On stimulating the motor cortex 3 cm anterior and 3 cm lateral to Cz, a scalp site remote from the primary motor area, ipsilateral motor evoked potentials (iMEPs) from hand muscles were found in recovered patients. (2) In 8 controls iMEPs with smaller amplitudes than patients could be obtained by stimulating only the left hemisphere. (3) TCD revealed increased blood flow velocity in the ipsilateral MCA by activating the recovering hand (10.5+/-3.3%; P<0.001). CONCLUSION: TMS reveals a specific area in the motor cortex from which ipsilateral MEPs can be elicited and both TMS and TCD indicate that an ipsilateral corticospinal tract can be accessible in some adult controls or becomes unmasked after cerebral damage.

Motor cortex excitability in chronic fatigue syndrome.

OBJECTIVE: To use transcranial magnetic stimulation (TMS) to define motor cortical excitability in chronic fatigue syndrome (CFS) subjects during a repetitive, bilateral finger movement task. METHODS: A total of 14 CFS patients were tested and compared with 14 age-matched healthy control subjects. TMS of the motor cortex (5% above threshold) was used to elicit motor evoked potentials (MEPs). Subjects performed regular (3-4/s) repetitive bilateral opening-closing movements of the index finger onto the thumb. MEPs of the first dorsal interosseus (FDI) were measured before, immediately following exercise periods of 30, 60 and 90 s, and after 15 min of rest. RESULTS: Performance, defined by rate of movement, was significantly slower in CFS subjects (3.5/s) than in controls (4. 0/s) independent of the hand measured. The rate, however, was not significantly affected by the exercise duration for either group. The threshold of TMS to evoke MEPs from the FDI muscle was significantly higher in CFS than in control subjects, independent of the hemisphere tested. A transient post-exercise facilitation of MEP amplitudes immediately after the exercise periods was present in controls independent of the hemisphere tested, but was absent in CFS subjects. A delayed facilitation of MEPs after 15-30 min of rest was restricted to the non-dominant hemisphere in controls; delayed facilitation was absent in CFS subjects. CONCLUSIONS: Individuals with CFS do not show the normal fluctuations of motor cortical excitability that accompany and follow non-fatiguing repetitive bimanual finger movements.

Delayed facilitation of motor cortical excitability following repetitive finger movements.

OBJECTIVES: To define motor cortical excitability changes occurring at various times after non-fatiguing bimanual exercise of the index fingers. METHODS: Twenty healthy right-handed subjects were studied with transcranial magnetic stimulation (TMS) of the right non-dominant hemisphere. They performed regular (3-4/s) repetitive opening-closing bilateral movements of the index finger onto the thumb. Motor evoked potentials (MEPs) of the left first dorsal interosseus (FDI) and rate of the repetitive finger movements were determined (1) before exercise, (2) immediately following 3 exercise periods of 30, 60 and 90 s, and (3) over a subsequent 30 min rest period. RESULTS: Rate of movement did not show significant change during any of the exercise periods but did increase significantly when tested after 15 min of rest. MEPs immediately after 30 and 60 s of exercise were facilitated whereas MEPs after 90 s of exercise did not differ from baseline measures. MEP amplitudes were significantly increased after rest of approximately 15 min compared to the baseline MEPs. In contrast, motor potentials evoked by peripheral nerve stimulation were unchanged throughout the experimental test periods. CONCLUSIONS: Motor cortical excitability relating to an intrinsic finger muscle (FDI) was facilitated beginning 15 min after a brief period of non-forceful, repetitive activity of that muscle. This delayed facilitation of motor cortex after exercise may represent a form of short-term potentiation of motor cortical excitability.

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.

The effect of riluzole in amyotrophic lateral sclerosis: a study with cortical stimulation.

A population of 31 patients with sporadic amyotrophic lateral sclerosis (ALS) was selected for a prospective open study based on treatment with riluzole. A neurophysiological evaluation was performed by means of single and paired transcranial magnetic stimulation (TMS). The examined parameters, excitability threshold, motor evoked potential (MEP) duration, silent period (SP) duration and time course of intracortical inhibition to paired TMS after 6 months treatment, were matched against those recorded from the patients themselves before the beginning of treatment and from 20 (single TMS) or 10 (paired TMS) age-matched control subjects. Normal behaviour of the SP in response to increasing TMS was found in the treated patients; they showed a significant linear correlation between these two parameters (r=0.96) comparable to that calculated for controls (r=0.98), and significantly different with respect to drug-free patients (r=0.8, P=0.014). A significant reduced size of the 'conditioned' MEPs to paired stimulation was documented in the treated patients compared with the untreated patients (P=0.002). Our neurophysiological contribution to the assessment of the effect of riluzole on the motor cortical inhibitory property in ALS may be considered a setting for controlled trials in extended patient series, even in a pre-clinical phase.

The effect of benzodiazepines and flumazenil on motor cortical excitability in the human brain.

In the present study, the effects of benzodiazepines (diazepam) were evaluated in terms of cortical excitability changes, as tested with transcranial magnetic simulation (TMS). In particular, analyzed were drug-induced changes regarding two selected parameters of TMS: (1) the cortical excitability threshold and (2) the silent period duration (SP). For this purpose, we evaluated the effects of long-term therapy with diazepam in the patients affected by anxiety disorders and the changes induced by single oral doses of diazepam in both healthy controls and patients. In addition, we tested cortical excitability changes in two 'extreme conditions' where a considerable concentration of serum benzodiazepine-like activity was reached, as represented by diazepam overdose and idiopathic recurrent stupor (IRS). In both groups of patients, a significant increment of motor threshold was found, while in the overdose patients, the SP was also increased. The administration of flumazenil in these two conditions was followed by a prompt reversal effect, consisting of a return to normal cortical excitability parameters. The long-term usage of diazepam in patients with anxiety disorders is associated with significantly increased threshold; the increased value of these parameters was temporarily further enhanced by the administration of a single oral dose of diazepam, which, in normal control subjects, is not associated with changes of cortical excitability. The results of this study reveal that different physio-pathological conditions induced by the influence of benzodiazepine and its antagonist are reflected in excitability changes which attest to the involvement and modification of cortical GABAergic activity.

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.

Towards a neurophysiological marker of amyotrophic lateral sclerosis as revealed by changes in cortical excitability.

Motor evoked potentials (MEPs) to magnetic trans cranial stimulation (TCS) were recorded in 47 patients with amyotrophic lateral sclerosis (ALS) in order to evaluate both excitability and conductivity changes relating to central motor pathways. The results were compared with those obtained from a control population of 43 subjects, 34 patients with definite multiple sclerosis (MS) and 15 patients with a rigid early from of Parkinson's disease (PD). The excitability threshold to TCS was higher in ALS patients for both upper and lower limbs compared with both controls and PD patients, but lower than that of MS patients. The Silent Period duration (SP (hand recordings): 80.1 ms, SD: 38.5) was significantly shorter in ALS patients than in all the other examined subjects (P < 0.001), nor did it increase proportionally to TCS intensity as with control subjects. The abnormal behavior of the SP appears to be specifically linked to the ALS disease, since it was neither observed in PD patients, nor in those with multiple sclerosis, who, on the contrary, displayed a prolonged mean duration of the SP (161.6 ms, SD 77 vs. 115.7 ms, SD 62 for the control group). Due to the neuronal loss of the largest neurons in ALS, MEP latency, amplitude, duration and the motor central conduction time (CCT) were in different proportion found abnormal. Our study shows how different neurological diseases with central motor involvement share broadly similar MEP abnormalities, but a different involvement of the silent period. We suggest that in ALS patients there may be abnormalities of motor cortical inhibitory mechanisms which are detected with the measurement of the SP. The distinctive 'depression' of this parameter in the case of ALS could be a significant marker for diagnosing this disease.

Cerebral plasticity after stroke as revealed by ipsilateral responses to magnetic stimulation.

The present study aims to provide neurophysiological evidence of ipsilateral activation during motor recovery in patients after stroke. The effects of cortical reorganization were investigated using magnetic brain stimulation in order to record motor evoked potentials (MEPs) both from contralateral and ipsilateral hands. Ten healthy subjects and 13 patients were examined. The patients had suffered their first hemispheric stroke and consequent motor deficit. While ipsilateral responses (iMEPs) were absent in normal subjects, they were obtained from both ipsilateral and contralateral hands in patients. The ipsilateral MEP differed from contralateral MEP in the following respects: (1) elicitation during contraction; (2) a shorter latency; (3) a lower amplitude. The presence of optimal iMEPs (lower excitability threshold, larger amplitude) in recovered hands points to a role for the undamaged hemisphere, and in particular to the involvement of secondary motor areas. We suggest that iMEPs in general may be a marker of brain plasticity, and that the specific type described here appear in the context of fast autochthonous motor recovery.

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.

Magnetic transcranial stimulation in healthy humans: influence on the behavior of upper limb motor units.

Aim of the study was to analyze the characteristics of motor action potentials recruitment during magnetic trans-cranial stimulation (TCS) of the brain. Coaxial needle recordings from hand and upper limb musculature, as well as surface electrodes were employed in 20 healthy controls during magnetic TCS with regular and figure-of-8 coil in different experimental protocols including: (a) simple reaction time paradigm during which TCS at subthreshold intensity for eliciting MEPs in relaxation was delivered at various intervals between the signal to move and the onset of the voluntary EMG burst; (b) suprathreshold TCS was randomly delivered while the subject was voluntarily firing at a regular rate one 'low' and/or 'high threshold' motor unit action potential (MUAP). The pre- and post-TCS MUAPs recruitment as well as their firing rates were compared; (c) recordings with two separate needles picking up individual MUAPs from the same or from two different muscles were obtained in order to test 'synchrony' of MUAP's discharge before and after TCS; (d) the influence of the time-interval separating the last discharged MUAP from TCS was evaluated. (e) differences between simultaneous surface and depth recordings were examined. The following results were obtained. (a) The same low-amplitude MUAP which is first voluntarily recruited at the onset of the EMG burst is the one initially fired by TCS in the pre-movement period. Latency shortenings and amplitude enlargement of surface MEPs were observed with faster reaction times. Such changes were coupled to the recruitment of high-threshold MUAPs being larger in amplitude and briefer in latency than the initial one. (b) When using suprathreshold TCS, MEPs followed by silent periods were found. The SP was followed by a rebound acceleration of the MUAPs firing rate compared with pre-TCS levels. Besides rebound acceleration, new MUAPs of larger amplitude than the original (= pre-stimulus) ones were recruited beyond the voluntary control. This phenomenon-together with longer SPs- was progressively more pronounced with stronger stimuli. (c) TCS was affecting the 'synchrony' of MUAPs. (d) If the latency difference between the last pre-stimulus spike and the TCS was exceeding the half-cycle of the MUAP 'natural' firing, the SP was longer in duration. (e) SPs not preceded by MEPs were clearly present in depth recordings. Surface recordings mainly reflected the behavior of high-threshold and large MUAPs.

Corticocortical inhibition in human motor cortex.

1. In ten normal volunteers, a transcranial magnetic or electric stimulus that was subthreshold for evoking an EMG response in relaxed muscles was used to condition responses evoked by a later, suprathreshold magnetic or electric test shock. In most experiments the test stimulus was given to the lateral part of the motor strip in order to evoke EMG responses in the first dorsal interosseous muscle (FDI). 2. A magnetic conditioning stimulus over the hand area of cortex could suppress responses produced in the relaxed FDI by a suprathreshold magnetic test stimulus at interstimulus intervals of 1-6 ms. At interstimulus intervals of 10 and 15 ms, the test response was facilitated. 3. Using a focal magnetic stimulus we explored the effects of moving the conditioning stimulus to different scalp locations while maintaining the magnetic test coil at one site. If the conditioning coil was moved anterior or posterior to the motor strip there was less suppression of test responses in the FDI. In contrast, stimulation at the vertex could suppress FDI responses by an amount comparable to that seen with stimulation over the hand area. With the positions of the two coils reversed, conditioning stimuli over the hand area suppressed responses evoked in leg muscles by vertex test shocks. 4. The intensity of both conditioning and test shocks influenced the amount of suppression. Small test responses were more readily suppressed than large responses. The best suppression was seen with small conditioning stimuli (0.7-0.9 times motor threshold in relaxed muscle); increasing the intensity to motor threshold or above resulted in less suppression or even facilitation. 5. Two experiments suggested that the suppression was produced by an action on cortical, rather than spinal excitability. First, a magnetic conditioning stimulus over the hand area failed to produce any suppression of responses evoked in active hand muscles by a small (approximately 200 V, 50 microsecond time constant) anodal electric test shock. Second, a vertex conditioning shock had no effect on forearm flexor H reflexes even though responses in the same muscles produced by magnetic cortical test shocks were readily suppressed at appropriate interstimulus intervals. 6. Small anodal electric conditioning stimuli were much less effective in suppressing magnetic test responses than either magnetic or cathodal electric conditioning shocks.(ABSTRACT TRUNCATED AT 400 WORDS)

Latency jump of "relaxed" versus "contracted" motor evoked potentials as a marker of cortico-spinal maturation.

Magnetic brain stimulation was carried out in 17 children, aged from 2 to 12 years, in order to investigate the latency difference between relaxed and contracted motor evoked potentials (MEPs) as a function of age. While the latency of contracted MEPs increased in a linear fashion with age and body size, the relaxed MEP latency had a much slower "maturation," which gained the adult value at about 10-12 years of age in parallel with the acquisition of manual skills. The age-related variation of this "latency jump" appears to be a specific indicator of maturative phenomena relating to motor systems.

Central conduction studies and magnetic stimulation.

Magnetic stimulation of brain and spinal roots provides non-invasive evaluation of the propagation of nerve impulses as well as characteristics of excitability along the motor pathways. Physiology of motor performances and pathophysiology of movement disorders can be approached with this new technique. Moreover, transcranial stimulation (TCS) of non-motor areas of the brain represents a formidable probe for the evaluation of lateralized hemispheric properties connected with higher cortical functions.

Age-related changes of motor evoked potentials in healthy humans: non-invasive evaluation of central and peripheral motor tracts excitability and conductivity.

A comparative analysis of the corticospinal tract nervous propagation and excitability threshold was carried out in young (25 subjects, age range 16-35 years) and in elderly (40 subjects, 51-86 years) populations of healthy volunteers. Motor evoked potentials (MEPs) were recorded from the hand and foot muscles following transcranial magnetic stimulation (TCS) during complete relaxation and active contraction of the target muscles. Threshold intensities corresponded to the stimulator's output eliciting liminal MEPs in about 50% of stimuli during relaxation. It was found that threshold values of magnetic TCS were significantly higher in the elderly (44 +/- 6.4% vs 39 +/- 3.5% for the hand; 66 +/- 10.1% vs 56 +/- 6.7% for the foot; P < 0.001) than in the young subjects. Moreover, this index progressively increased with age (P < 0.001), whilst the propagation time along the central motor tracts did not parallel such an age-related trend.

Brain excitability and long latency muscular arm responses: non-invasive evaluation in healthy and parkinsonian subjects.

Thirty healthy and 35 volunteers affected by Parkinson's disease (PD) were examined. Long latency responses (LLRs) and short latency somatosensory evoked potentials (SEPs) after median nerve stimulation were respectively recorded from forearm flexor muscles, and from 19 scalp electrodes, during relaxation (condition 1), light and maximal muscle contraction (conditions 2 and 3). Linear interpolation of SEPs was performed to produce isopotential colour maps. Latencies and amplitudes of the V1-V2 component in LLR, as well as of parietal, central and frontal scalp SEPs were analysed in the 3 experimental conditions. Highly significant inverse correlation matched the frontal SEP to the LLR V2 component amplitudes, both in healthy and in PD subjects. However, the V2 component--which in the former group was reliably identifiable only in condition 3--was presented in conditions 1 and 2 in a high percentage of PD subjects who also showed an abnormally reduced frontal SEP during complete relaxation. Excitability changes of brain motor areas induced by a sensory input were tested as follows: the motor cortex was transcranially stimulated (TCS) by magnetic pulses with an intensity 10% below (A) or above (B) the threshold for twitch elicitation during complete relaxation of forearm muscles; TCS was randomly preceded (range 14-32 msec) by a shock to the median or ulnar nerve at the elbow with identical characteristics as for LLR elicitation. An initial epoch of 'inhibition' followed by a peak of 'facilitation' of the amplitude of motor responses to TCS was observed when conditioning stimuli to the median nerve preceded TCS by 14-20 and by 24-32 msec, respectively. Contrary to normals, conditioning stimulation of the median nerve did not significantly influence the excitability threshold to TCS in those parkinsonians with depressed frontal N30.