Vigilance troubles in Parkinson's disease: a subjective and objective polysomnographic study.

BACKGROUND AND PURPOSE: To assess the prevalence of vigilance disorders in Parkinson's disease patients, relate the observed phenomena to potential causes and confirm these troubles with polysomnographic analysis. PATIENTS AND METHODS: A questionnaire was used to gather information on demographic data, previous and current treatments, disease characteristics, sleep and vigilance troubles. Somnolence was measured using the Epworth Sleepiness Scale (ESS). Nocturnal polysomnography (PSG) and multiple sleep latency tests (MSLT) were performed for a sample of parkinsonian patients. RESULTS: Two hundred twenty-two parkinsonian patients completed the questionnaire, and 36 patients had objective analyses. Of the patients, 43.2% had an ESS score >10, and 28.4% reported somnolence in the hour after taking dopaminergic drugs, whereas 6.8% reported unintended sleep episodes. In view of questionnaire data, these vigilance disorders may be partly explained not only by the impact of nocturnal sleep disorders (e.g. sleep apnea syndromes) but also by dopaminergic therapy (especially with dopaminergic agonists). With PSG and MSLT results, we have shown a significant correlation between mean sleep latency and ESS score. Patients with unintended sleep episodes have severe sleepiness in MSLT compared with others patients. CONCLUSIONS: Vigilance disorders are frequently observed in Parkinson's disease. We recommend informing patients of the risk of occurrence of such conditions, notably for patients with unintended sleep episodes and with sleepiness in the hour after taking dopaminergic drugs.

Effects of bilateral subthalamic stimulation on sleep in Parkinson's disease.

OBJECTIVE: Sleep disturbances are frequently observed in Parkinson's disease (PD). Bilateral chronic subthalamic nucleus (STN) stimulation is an alternative treatment for advanced PD. Improvements in motor disturbances after STN stimulation are well documented and seem to be associated with better sleep quality, even though the objective effect on sleep structure remains unclear. We have therefore studied the sleep/wakefulness cycle before and after surgical treatment in 10 consecutive parkinsonian patients. METHODS: Subjective sleep quality and sleep recordings were evaluated one month before and three months after initiation of STN stimulation. After surgery, the recordings were performed under two conditions: with stimulation (the "on" condition) and-if patients had given their consent-in the absence of stimulation (the "off" condition). RESULTS: With STN stimulation, subjective and objective sleep qualities were improved. Total sleep time, sleep efficiency and the durations of deep slow wave sleep and paradoxical sleep increased significantly. When stimulation was absent, sleep disturbances were similar to those observed before surgery. CONCLUSION: Chronic STN stimulation is associated with a sleep improvement, which can be explained in part by the concomitant decrease in motor disturbances but also by the reduction in dosages of antiparkinsonian medication. However, we can not exclude a direct effect of STN stimulation on sleep regulatory centres.

Subthalamic nucleus stimulation modulates motor cortex oscillatory activity in Parkinson's disease.

In Parkinson's disease, impaired motor preparation has been related to an increased latency in the appearance of movement-related desynchronization (MRD) throughout the contralateral primary sensorimotor (PSM) cortex. Internal globus pallidus (GPi) stimulation improved movement desynchronization over the PSM cortex during movement execution but failed to improve impaired motor preparation. PET studies indicate that subthalamic nucleus (STN) stimulation partly reverses the abnormal premotor pattern of brain activation during movement. By monitoring MRD, we aimed to assess changes in premotor and PSM cortex oscillatory activity induced by bilateral STN stimulation and to compare these changes with those induced by l-dopa. Ten Parkinson's disease patients and a group of healthy, age-matched controls performed self-paced wrist flexions in each of four conditions: without either stimulation or l-dopa (the 'off' condition), with stimulation and without l-dopa (On Stim), with l-dopa and without stimulation ('on drug'), and with both stimulation and l-dopa (On Both). Compared with the Off condition, in both the On Stim and the On Drug condition the Unified Parkinson's Disease Rating Scale (UPDRS) III score decreased by about 60% and in the On Both condition it decreased by 80%. The desynchronization latency over central regions contralateral to movement and the movement desynchronization over bilateral central regions were significantly increased by stimulation and by l-dopa, with a maximal effect when the two were associated. Furthermore, desynchronization latency significantly decreased over bilateral frontocentral regions in the three treatment conditions compared with the Off condition. In Parkinson's disease, STN stimulation may induce a change in abnormal cortical oscillatory activity patterns (similar to that produced by l-dopa) by decreasing the abnormal spreading of desynchronization over frontocentral regions and increasing PSM cortex activity during movement preparation and execution, with a correlated improvement in bradykinesia. Parkinsonians under treatment displayed a desynchronization pattern close to that seen in healthy, age-matched controls, although central latencies remained shorter. The study indicates that it is possible to influence cortical reactivity related to the planning and execution of voluntary movement through the basal ganglia, and furthermore that the oscillatory activity of the PSM cortex (in addition to that of premotor areas) could be of major importance in the control of movement-associated, neural activity in Parkinson's disease.

Motor preparation is more impaired in Parkinson's disease when sensorimotor integration is involved.

OBJECTIVE: This study aimed to investigate changes in spatio-temporal, event-related (de)synchronization (ERD/ERS) patterns recorded with respect to the more akinetic versus the less akinetic side during performance of a visuo-guided targeting movement when compared to an index finger extension. METHODS: Twelve de novo parkinsonian patients were recorded. ERD/ERS in mu and beta frequency bands was computed from 21 source derivations. RESULTS: When the index finger extension was performed with the less akinetic limb, mu ERD focused over contralateral central region appeared 2 s before movement. With the targeting movement, additional pre-movement mu ERD was observed over the parietal region, as well as earlier ipsilateral mu ERD. When the same movements were performed with the more akinetic limb, we observed delayed mu ERD over contralateral regions, earlier ipsilateral mu ERD and a lack of contralateral parietal mu ERD before the targeting movement. Following index finger extension for the less akinetic limb, a focused contralateral central beta ERS was recorded, increasing and spreading after the targeting movement. In contrast, for the more akinetic limb, beta ERS was dramatically attenuated and remained unchanged after the targeting movement. CONCLUSIONS: These results confirm the fact that motor programming is delayed, and provide some insight into what may well be impaired sensorimotor integration in Parkinson's disease.

Effect of L-Dopa on the pattern of movement-related (de)synchronisation in advanced Parkinson's disease.

In the early stages of Parkinson's disease (PD), impaired motor preparation has been related to a delay of mu rhythm movement-related desynchronisation, suggesting hypoactivation of the contralateral, primary sensorimotor (PSM) cortex. Following movement, a decrease in the amplitude of beta rhythm movement-related synchronisation was observed over the same region. This decrease--not seen in control subjects--was thus thought to be related to an impairment in cortical deactivation. By monitoring movement-related (de)synchronisation, we aimed (i) to extend to advanced PD the observations made in less-advanced situations and (ii) to test the effect of acute L-Dopa on these abnormalities. The United Parkinson's Disease Rating Scale (UPDRS) III score decreased by about 60% following acute L-Dopa administration, and we observed the following concurrent changes: a marked increase in mu desynchronisation pre-movement latency (thus reduced delay) during movement preparation over contralateral, central regions; an increase in mu desynchronisation during movement execution over bilateral central regions; a decrease in mu desynchronisation latency over bilateral frontocentral regions, and a significant increase in beta synchronisation over contralateral, central regions after movement. Changes of mu and beta rhythm parameters seemed to be inversely correlated with bradykinesia. Mu rhythm desynchronisation latency and beta synchronisation amplitude further decreased in advanced PD compared to earlier stages of the disease, suggesting greater impairment of cortical activation/deactivation as the disease progresses. L-Dopa partially restored the abnormal mu and beta rhythm cortical (de)synchronisation patterns over the PSM cortex.

Subthalamic stimulation influences postmovement cortical somatosensory processing in Parkinson's disease.

In Parkinson's disease, poor motor performance (resulting primarily from abnormal cortical activation during movement preparation and execution) may also be due to impaired sensorimotor integration and defective cortical activity termination of the ongoing movement, thus delaying preparation of the following one. Reduced movement-related synchronization of the beta rhythm in Parkinson's disease compared to controls has been put forward as evidence for impaired postmovement cortical deactivation. We assessed the effects of subthalamic deep brain stimulation and l-dopa on beta rhythm synchronization over the premotor and primary sensorimotor cortex. Ten advanced patients performed self-paced wrist flexion in four conditions according to the presence or not of stimulation and l-dopa. Compared to without treatment, the motor score improved by approximately 60%; the beta synchronization was present over the contralateral frontocentral region and increased significantly over the contralateral central region under stimulation and under l-dopa, with a maximal effect when both treatments were associated. Our advanced patients displayed very focused and attenuated beta rhythm synchronization which, under stimulation, increased over the contralateral premotor and primary sensorimotor cortex. Stimulation and l-dopa both partly restored postmovement cortical deactivation in advanced Parkinson's disease, although the respective mechanisms probably differ. They may improve bradykinesia and cortical deactivation by reestablishing movement-related somatosensory processing at the end of the movement through the basal ganglia into the cortex.

Heart rate variability and Parkinson's disease severity.

Heart rate variability (HRV) decrease in Parkinson's disease (PD) could only be a consequence of reduce motor activity besides of being a marker of cardiovascular dysautonomia. Under continuously recorded and standardised motor activity, we studied thirty patients compared to controls in 3 PD stages: group I: less than 2 year-evolution, slight impaired without L-dopa; group II: mildly impaired with L-dopa; group III: advanced PD with motor complications. No difference was observed between group I and controls. The diurnal low frequency power (LF) and the ratio of LF/high frequency (HF) power decreased in groups II and III. The nocturnal vagal indicators: HF power and pNN50 were decreased in group III. Those parameters were correlated with Off-drug-motor handicap, suggesting an evolutive HRV decrease with disease severity but not with On-drug-motor activity. The low LF despite the higher motor activity in group III, due to dyskinesias, suggested a defective cardiovascular up-regulation.

Changes in oscillatory cortical activity related to a visuomotor task in young and elderly healthy subjects.

OBJECTIVE: In order to better understand the spatio-temporal interaction of the activated cortical areas when the movement is visuo-guided and to assess the age effect on the spatio-temporal pattern of cortical activity, we have compared a proximo-distal movement with visual-motor control and hand-eye coordination (targeting movement) with a distal and a proximal movement. METHODS: Brain's electrical activity was studied using the analysis of event-related (de)synchronizations (ERD/S) of cortical mu and beta rhythms in 17 subjects, 8 young and 9 elderly subjects. RESULTS: In both populations, we found an earlier and broader mu and beta ERD during the preparation of the targeting movement compared to distal and proximal movements, principally involving the contralateral parietal region. During the execution, a spreading over the parietocentral region during proximal movement and over the parietal region during targeting movement was observed. After the execution of proximal and targeting movements, a wider and higher beta ERS was observed only in the young subjects. In the elderly subjects, our results showed a significant decrease of beta ERS during the targeting task. CONCLUSIONS: These results suggest there was a larger recruitment of cortical areas, involving notably the parietal cortex when the movement is visuo-guided. Moreover, cerebral aging-related changes in the spatio-temporal beta ERS pattern suggests an impaired sensory integration.

[Clinical and electrophysiological features of "cortical tremor"]. / Caractéristiques cliniques et électrophysiologiques du << tremblement cortical >>.

The purpose of this paper is to draw attention to one particular variant of tremor named "cortical tremor," which corresponds to rhythmic cortical myoclonus whose principal differential diagnosis is essential tremor. Diagnosis may be established with electrophysiological explorations (electromyography, accelerometry, electroencelography with back averaging, long latency reflexes, giant somesthesic evoked potentials). Clinical and electrophysiological features of 15 patients are reported and compared to cases previously published. Association with generalized or partial seizures is possible. Other cases in the family are often mentioned with a dominant autosomal transmission. The therapeutic approach is based on the use of antiepileptic drugs.

Study of circadian melatonin secretion pattern at different stages of Parkinson's disease.

To explore changes in melatonin secretion patterns and biologic rhythms in Parkinson's disease patients with or without levodopa-related motor complications (LDRMCs), the authors investigated, in an observational study, circadian rhythms of central temperature, motor activity, plasma cortisol, and melatonin in three groups: de novo untreated patients (group I), patients treated with levodopa + dopamine agonist and without LDRMCs (group II), and patients treated with levodopa + dopamine agonist and with LDRMCs (group III). There were no differences among the three groups for the rhythm of temperature, motor activity, or plasma cortisol. There was a significant (p < 0.05) phase advance in plasma melatonin secretion in patients receiving a dopaminergic treatment compared with untreated patients. The daytime area under the curve (AUC) was increased significantly in group III, and the nighttime AUC-to-daytime AUC ratio of melatonin secretion decreased significantly in group III, suggesting that the nychthemeral pattern of melatonin secretion was changed in patients with LDRMCs. Comparison of the three groups suggests a slight but insignificant phase advance and amplitude decrease of circadian melatonin secretion related to both evolution and treatment of Parkinson's disease. Despite the lack of a global desynchronization in other circadian biologic rhythms, the circadian secretion pattern of melatonin is modified in patients with LDRMCs.

[Parkinson's disease as a model of aging: prospective analysis of gait discorders]. / Maladie de Parkinson comme modèle de vieillissement: analyse prospective des troubles de la marche.

Falls are a dramatic consequence of the age-related gait disorders. There are few prospective studies on falls predictive of the biomechanical features of gait. According to the literature, there are similarities between the gait observed in older people and in parkinsonian subjects. The objective of this study was to apply multiparametric gait analysis to demonstrate changes of the neuromotor gait pattern connected with falls. This prospective study included two groups of 16 subjects aged more than 60 years, who had not fallen during the previous year. One group included 16 minimally disabled parkinsonian patients off drugs, and the other group 16 healthy people. Gait recordings were obtained with a three-dimensional optoelectronic movement analysis system coupled with 2 force platforms in all persons who were followed for 1 year to collect data on all new events, particularly falls. Data analysis concerned spatiotemporal stride and three-dimensional power peaks developed in each lower limb joint. Cluster analysis of the 32 persons was used to determine various infraclinic neuromotor gait patterns. A post hoc analysis of variance was then applied to identify discriminating parameters. Three groups of subjects were identified with 3 different neuromotor gait patterns, independently of the presence of Parkinson disease. There were no fallers in first group (n=18). The second group (n=8) had 20 p.cent fallers and the third group (n=4) 100 p.cent fallers. The groups differed by 4 spatiotemporal parameters and 3 joint power peaks in the sagittal plane. Functional capacity was good in the first group with no falls recorded. This group of subjects had characteristics reported in the literature corresponding to a category of persons who compensate well for the phenomena of aging. Functional capacity was intermediary in the second group (20 p. cent were fallers). The kinematic pattern appeared to be less successful, revealing a tendency for stiff posture. The third group (100 p. cent fallers) exhibited inferior functional capacity. In this group, the kinematic pattern appeared to be disrupted. The subjects were unable to adapt satisfactorily to situations other than by stereotypical neuromotor reactions. In conclusion this study demonstrated a close determinism between physiological neuromotor aging and Parkinson's disease. The prospective follow-up demonstrated that falls that occurred were related to changes in neuromotor gait patterns. Three phases of gait pattern were also identified from minimal to major risk of falls.

[Postural strategies and falls in elderly and in parkinsonism]. / Stratégies posturales et chutes chez la personne âgée et le sujet parkinsonien.

OBJECTIVE: To use a posture analysis to show the evolution of postural pattern connected with falls. MATERIAL AND METHOD: It is a prospective study on two groups of 16 persons of more than 60 years. A group concerns 16 small disability off drug parkinsonian patients, a group concerns 16 healthy witnesses. All the persons benefited from a posture recording by means of a force platform and were followed during 1 year. RESULTS: Data analysis underlines three groups of persons corresponding to three postural patterns, independently of the presence of Parkinson disease. A group (n = 18) did not contain fallers, the second (n = 10 ) contained 20% of fallers, the third (n = 4) contained 100% of fallers. Differences between the groups were identified on 16 posturographic parameters. DISCUSSION: A group has a good functional value and one does not record any fall. Its characteristics, which correspond to a category of persons who compensate well for the phenomena of ageing, are found in the literature. A group has an intermediate functional value and regrets 20% of fallers. Kinetic profile reveals a tendency to the stiffness of the posture. This group is going to operate rather ankle strategies. A group has an inferior functional value and regrets 100% of fallers. Kinetic profile seems disrupted and not to be able to adapt itself in a satisfactory way to the situation otherwise than by stereotypical reactions. This group is going to operate systematically much less stabilizing hip strategies. CONCLUSION: A close determinism between physiological neuromotor ageing and Parkinson disease does exist. We showed with a prospective follow-up, the arisen of fall and showed the evolution of postural patterns related to fall. It appears as well that evolution mainly follows three stages leading from a small risk of fall gait pattern to a major risk of fall gait pattern.

[Characterization of the functional relations between cerebral structures: the linear and non-linear]. / Caractérisation des relations fonctionnelles entre structures cérébrales: du linéaire au non linéaire.

Two kinds of methods are available in order to assess the functional relationships between different cerebral structures from the analysis of EEG signals: linear and non-linear methods. In this paper, we describe didactically the methodological bases of signal processing. After recalling the significance of the fundamental parameters of a sine wave: frequency, amplitude and phase, we show, from a first example about an epileptic seizure propagation, how a linear variation between phase and frequency can be interpreted as a small time difference between two EEG channels. This linear method hypothesises that these two signals are respectively the input and the output of a linear system. Then, we point out the limits of this method and we introduce non-linear methods. Among the latter, a recent approach introduces a realistic model of EEG which try to relate signal measured quantities to relations between underlying structures which produce them.

Influence of internal globus pallidus stimulation on motor cortex activation pattern in Parkinson's disease.

OBJECTIVES: Indications of the functional neurosurgical treatments become more and more numerous, however, few methods were used to study the mechanism of action and some discrepancies came to light. We assessed the influence of internal globus pallidus (GPI) stimulation and L-Dopa on cortical activation during the preparation and execution phases of the movement compared to clinical improvement of Parkinson's disease. METHODS: We recorded the movement-related cortical potential and movement-related desynchronization. RESULTS: The Unified Parkinson's Disease Rating Scale was improved by 46% under stimulation and 64% under stimulation with L-Dopa. Premovement desynchronization was significantly increased on central contralateral derivation under stimulation with L-Dopa and decreased on frontocentral ipsilateral derivation under stimulation with and without L-Dopa. Movement desynchronization was improved on the contralateral motor cortex under stimulation with and without L-Dopa (benefit correlated with bradykinesia improvement). The movement-related postmotor potential was significantly increased under stimulation with L-Dopa. CONCLUSIONS: GPI stimulation alone influenced the premotor cortex activation during the planning and induced a selective and focal effect on the organisation of motor cortical activity during the movement execution which may explain bradykinesia improvement. The motor cortex activation improvement under stimulation with L-Dopa concerned both the movement preparation and execution but remained very localised to the contralateral motor cortex.

Does post-movement beta synchronization reflect an idling motor cortex?

After the completion of a voluntary movement, a synchronization of cortical beta rhythms is recorded over the contralateral central region, which is assumed to reflect the termination of the motor command. In order to test this hypothesis, we compared in eight healthy subjects the synchronization of EEG beta rhythms following active and passive index extension. The passive movement was also performed after deafferentation by ischaemic nerve block in three subjects. Beta synchronization was present in all subjects after both active and passive movements, and disappeared under ischaemia in all three subjects. Post-movement beta synchronization can not solely be explained by an idling motor cortex. It may also, at least in part, reflect a movement-related somatosensory processing.

Autonomic dysfunction in multiple sclerosis: cervical spinal cord atrophy correlates.

Autonomic dysfunction has rarely been studied in patients suffering from multiple sclerosis (MS). Some hypotheses have concerned the pathophysiology, especially with regard to a possible spinal cord origin. However, there have been no previous studies on autonomic dysfunction in MS and spinal cord lesions. This study assessed the frequency of autonomic dysfunction (AD) in MS and the correlation to spinal cord magnetic resonance imaging (MRI) findings. We prospectively studied 75 MS patients (25 with relapsing-remitting forms, 25 with secondary progressive forms and 25 with primary progressive forms). We performed sympathetic skin response, R-R interval variability and orthostatic hypotension testing. Spinal cord MRI was performed to detect demyelinating lesions (sagittal and axial plane) or spinal cord atrophy. Clinical and laboratory evidence of AD was found in 84% and 56% of MS patients, respectively. The correlation of the latter with disability was evaluated using the Extended Disability Status Scale. AD was more frequent in primary progressive MS than in the other two forms. AD was correlated with spinal cord cross-sectional area reduction but not with spinal cord hyperintensities. This study confirms that the frequency of AD in MS, especially in primary progressive forms, has until now been underestimated. Furthermore, AD appears to be more closely related to axonal loss, as demonstrated by spinal cord atrophy, than to demyelinating lesions.

Event-related variations in the activity of EEG-rhythms. Application to the physiology and the pathology of movements.

The averaging of the ongoing activity of the electroencephalogram (EEG) allows extracting the potentials that are time-locked and phase-locked to an event. These potentials are described as evoked potentials. There is another type of change in the ongoing EEG, which is time-locked but not phase-locked to an event: the EEG rhythm reactivity, also called "Event-Related Desynchronization and Synchronization" (ERD/ERS) by Pfurtscheller. These changes are often visible to the naked eye but they cannot be extracted by the averaging technique. Their quantification requires another method, which was suggested by Pfurtscheller and Aranibar in 1977. This method consists in measuring the temporal evolution of the power of EEG signal within a given frequency band before, during, and after an event. ERD corresponds to the decrease in power of an EEG rhythm related to an event. Conversely, ERS corresponds to an increase in amplitude of an EEG rhythm related to the event. ERD represents the activation of the subjacent cortical areas. ERS would partly traduce the setting at rest of the cortex; it would also be related to the somesthetics afferents inputs. This method can be applied to the study of cortical activation in many situations: memory tasks, auditory processing, attention, anticipatory behavior, and voluntary movement. Thus, a voluntary self-paced movement of the dominant hand is preceded by an ERD of mu and beta rhythms occurring respectively 2 000 and 1 500 ms before the movement onset. This ERD is recorded over the contralateral central region. It becomes bilateral at the movement onset and reaches its maximum at the movement offset. It is then followed by an ERS of the beta rhythms. We show that ERD/ERS phenomena vary with the type of movement, and that their study allows exploring the modifications of cortical excitability that are observed in Parkinson's disease and in epilepsy with focal motor seizures.

Chronic bilateral pallidal stimulation and levodopa do not improve gait in the same way in Parkinson's disease: a study using a video motion analysis system.

Chronic bilateral internal globus pallidus (GPi) stimulation allows control of levodopa induced dyskinesias (LID) and motor symptoms in severe Parkinson's disease (PD). The effect on gait has not been clearly established. Different results have been reported, mostly consisting of clinical data. The aim of this study was to evaluate, by means of a video motion analysis system (optoelectronic VICON system), the influence of bilateral GPi stimulation on gait in PD. Five patients underwent bilateral GPi stimulation. The preoperative and postoperative (3 months after surgery) clinical gait disturbances (items 29 and 30 of the motor UPDRS), as well as spatial and temporal gait measurements (namely cadence, velocity, stride and step times, single and double limb support times, stride and step lengths) were analysed in off condition (the patient had received no treatment for 12 hours or merely the lowest dose of levodopa allowing him to walk for the gait analysis) and in the on drug condition (after administration of 200 mg of levodopa). The gait analysis was performed with the VICON system. In off condition, there was a statistically significant improvement after surgery for UPDRS III and gait (clinically assessed). In on drug condition, there was a significant improvement for LID whereas UPDRS III and clinical assessment of gait were unchanged. The VICON system also showed that surgery improved gait especially in off condition, but also in on drug condition. Our method allowed exact quantification of the influence of surgery on gait characteristics. As compared with levodopa treatment, the effect of stimulation seems to be different. Indeed, the results suggest only limited effects of pallidal stimulation on the control of stride length and rather point to compensatory additional mechanisms.

[Thulium laser evoked potentials. Normative values for the arms and legs]. / Les potentiels évoqués au laser thulium. Valeurs normatives aux membres supérieurs et inférieurs.

Laser somatosensory evoked potentials (LSEP) evaluate the functional integrity of thermoalgic pathways by the specific stimulation of A delta and C nociceptive afferences. As compared to a CO2 laser, the thulium Yttrium Aluminium Garnet (YAG) laser may be conducted by an optic fiber, which allows easier access to the stimulated body sites. We present normative data on thulium YAG LSEPs recorded after stimulation of upper and lower limbs (N = 15). LSEPs were obtained with a stimulation intensity that was twice the nociceptive threshold at the upper limbs (UL) and one and a half at the lower limbs (LL). To ensure a stable attentional level, subjects were asked to estimate stimulus intensity after each stimulation. The nociceptive thresholds at upper and lower limbs were respectively 319 +/- 65 mJ and 359 +/- 95, and with the above methodology the LSEPs could be obtained in every subject. The latencies of N2 and P2 were respectively 199 +/- 18 ms and 325 +/- 37 ms at the UL, 239 +/- 36 ms and 378 +/- 38 ms at the LL. This method produced robust and reproducible results and proved to be reliable for routine clinical use. To optimise response stability we propose that right/left stimulation be conducted following an 'A-B-B-A' procedure.