Changes in motor unit numbers in patients with ALS: a longitudinal study using the adapted multiple point stimulation method.

METHOD: The adapted multiple point stimulation (AMPS) method for calculating motor unit numbers (MUNE) was applied in 12 patients with amyotrophic lateral sclerosis (ALS) before riluzole therapy (T(0)) and again after 4, 8 and 12 months of treatment. RESULTS: Paired Student's t-test indicated a significant decrease of thenar MUNE and compound muscle action potential (CMAP) size at each 4-monthly interval, while average surface motor unit potential (SMUP) size did not change significantly over time. The rate of motor unit (MU) loss at month 4 was more than 20% in six patients (group 1) and less than 20% in six other patients (group 2). Comparison of groups 1 and 2 by Mann-Whitney U-testing indicated that percent changes in thenar MUNE and CMAP size compared to baseline were significantly different at months 4, 8 and 12, while no difference between the two groups was found for average SMUP size variations. In the group with a slow rate of MU loss, CMAP size remained stable, while in the group with a rapid rate of MU loss, there was a dramatic reduction in size of the CMAP. A positive correlation was found between percent change in thenar MUNE at T(4) and at T(12) (P < 0.001). CONCLUSION: AMPS is a useful technique to document MUNE, SMUP size and CMAP size changes over time in patients with ALS.

Reduced excitability of the motor cortex in untreated patients with de novo idiopathic "grand mal" seizures.

OBJECTIVES: Transcranial magnetic stimulation (TMS) was used to investigate motor cortex excitability, intracortical excitatory, and inhibitory pathways in 18 patients having experienced a first "grand mal" seizure within 48 hours of the electrophysiological test. All had normal brain MRI, and were free of any treatment, drug, or alcohol misuse. Results were compared with those of 35 age matched normal volunteers. METHODS: The following parameters of responses to TMS were measured: motor thresholds at rest and with voluntary contraction, amplitudes of responses, cortical silent periods, and responses to paired pulse stimulation with interstimulus intervals of 1 to 20 ms. RESULTS: In patients, there were significantly increased motor thresholds with normal amplitudes of motor evoked potentials (MEPs), suggesting decreased cortical excitability. Cortical silent periods were not significantly different from those of normal subjects. Paired TMS with short interstimulus intervals (1-5 ms) induced normal inhibition of test MEPs, suggesting preserved function of GABAergic intracortical inhibitory interneurons. On the contrary, the subsequent period of MEP facilitation found in normal subjects (ISIs of 6-20 ms) was markedly reduced in patients. This suggests the existence of abnormally prolonged intracortical inhibition or deficient intracortical excitation. In nine patients retested 2 to 4 weeks after the initial seizure, these abnormalities persisted, although to a lesser extent. CONCLUSION: The present findings together with abnormally high motor thresholds could represent protective mechanisms against the spread or recurrence of seizures.

Prognostic value of decremental responses to repetitive nerve stimulation in ALS patients.

Decrement of the thenar compound muscle action potentials (CMAP), after repetitive nerve stimulation (RNS) of the median nerve at 3 Hz, was evaluated in patients with ALS before riluzole therapy. CMAP size as well as motor unit number and size estimates were evaluated twice before and after 1 year of riluzole therapy. The correlation between decrement and CMAP size reduction per year was highly significant (r = 0.77), but no relationship could be demonstrated between decrement and other variables. The authors thus propose that decrement after RNS may be used as a predictor of further drop in CMAP size.

Ipsilateral motor responses to focal transcranial magnetic stimulation in healthy subjects and acute-stroke patients.

BACKGROUND AND PURPOSE: Prevalence and characteristics of ipsilateral upper limb motor-evoked potentials (MEPs) elicited by focal transcranial magnetic stimulation (TMS) were compared in healthy subjects and patients with acute stroke. METHODS: Sixteen healthy subjects and 25 patients with acute stroke underwent focal TMS at maximum stimulator output over motor and premotor cortices. If present, MEPs evoked in muscles ipsilateral to TMS were analyzed for latency, amplitude, shape, and center of gravity (ie, preferential coil location to elicit them). In stroke patients, possible relationships between early ipsilateral responses and functional outcome at 6 months were sought. RESULTS: With relaxed or slightly contracting target muscle, maximal TMS over the motor cortex failed to elicit ipsilateral MEPs in the first dorsal interosseous (FDI) or biceps of any of 16 normal subjects. In 5 of 8 healthy subjects tested, ipsilateral MEPs with latencies longer than contralateral MEPs were evoked in FDI muscle (in biceps, 6 of 8 subjects) during strong (>50% maximum) contraction of the target muscle. In 15 of 25 stroke patients, ipsilateral MEPs in the unaffected relaxed FDI (in biceps, 6 of 25 stroke patients) were evoked by stimulation of premotor areas of the affected hemisphere. Their latencies were shorter than those that MEPs evoked in the same muscle by stimulation of the motor cortex of the contralateral unaffected hemisphere. Such responses were never obtained in normal subjects and were mostly observed in patients with subcortical infarcts. Patients harboring these responses had slightly better bimanual dexterity after 6 months. CONCLUSIONS: Ipsilateral MEPs obtained in healthy individuals and stroke patients have different characteristics and probably different origins. In the former, they are probably conveyed via corticoreticulospinal or corticopropriospinal pathways, whereas in the latter, early ipsilateral MEPs could originate in hyperexcitable premotor areas.

Projections from basal ganglia to tegmentum: a subcortical route for explaining the pathophysiology of Parkinson's disease signs?

Functional changes in the organisation of neuronal circuitries are generally used to explain parkinsonian motor symptoms and levodopa-induced dyskinesias. Based on information from histology and neurophysiological microrecordings of specific basal ganglia nuclei, the most widely accepted scheme is based on a central loop which starts in the cerebral cortex, makes multiple relays in the basal ganglia, and returns to the cerebral cortex. Transcranial magnetic stimulation studies, however, reveal no significant differences in the excitability of the motor cortex between normal subjects and patients with Parkinson's disease. Furthermore, electrophysiological and audiospinal facilitation studies indicate that the activity of reticular nuclei is altered in Parkinson's disease. It therefore appears that a circuit with the cortex as the only recipient of basal ganglia output is an oversimplification. This paper explores the relationships between various basal ganglia nuclei and proposes a subcortical pathway via which modifications in the basal ganglia may influence motor function.

Absence of response to early transcranial magnetic stimulation in ischemic stroke patients: prognostic value for hand motor recovery.

BACKGROUND AND PURPOSE: Transcranial magnetic stimulation (TMS) has been proposed as a prognostic tool in stroke patients. Most of the previous studies agree in considering the presence of motor-evoked potentials (MEPs) in the first days after a stroke as an indicator of good outcome. In the present study, we have assessed the prognostic value of the absence of response to early TMS on hand motor recovery in stroke patients with complete hand palsy at onset due to ischemia in the area of the middle cerebral artery. METHODS: Fifteen patients submitted to TMS within 48 hours of stroke onset (defined as day 1) and again after 1 year. They were also evaluated clinically on day 1 by a scale derived from the Medical Research Council (MRC) and by the National Institutes of Health (NIH) stroke scale; they were reevaluated by the same scales and by Barthel Index on day 365. RESULTS: On day 1, all the patients had complete hand palsy and no response to TMS; their NIH scores showed great variability. After 1 year, 6 of 15 patients regained small and prolonged MEPs, together with a very poor and not functionally useful motor recovery. NIH scores were significantly improved. Barthel Index scores showed large interindividual differences and were not correlated with MRC scores. CONCLUSIONS: We conclude that in patients with complete hand palsy, the absence of response to TMS in the first hours is predictive of absent or very poor, not useful, hand motor recovery.

Motor cortex inhibition is not impaired in patients with Alzheimer's disease: evidence from paired transcranial magnetic stimulation.

Motor cortex excitability was studied by transcranial magnetic stimulation (TMS) in 17 patients with Alzheimer's disease (AD). Resting and active thresholds for TMS were significantly reduced in AD patients compared to young and aged healthy subjects. The maximum amplitude of the motor response evoked by TMS was also significantly increased in AD patients. We have tested if these changes are related to a modification of the short-lasting intracortical inhibition of the motor cortex by paired conditioning-test TMS. We found no significant differences between AD patients and aged healthy subjects even if there is a slight but significant difference between aged and young normal subjects. We conclude that the modification of excitability of the motor cortex does not result from an impaired intracortical inhibition.

Age-related changes in fastest and slowest conducting axons of thenar motor units.

Single thenar motor unit F waves (FMUPs) were collected from 23 healthy volunteers (age range 21-91 years, mean 46 +/- 20 SD). In each subject, 10 distinct FMUPs were recorded, using surface stimulating and recording electrodes, and the conduction velocity (CV) of each motor unit was calculated. The distribution of CVs (overall range 42-66 m/s; individual FMUP CV dispersion range 6-27% of the maximal FMUP CV) was close to those previously reported whatever the technique used. With age, a progressive CV reduction was observed, and maximal FMUP CV was significantly correlated with age (r = -0.58, P < 0.01), whereas no statistically significant correlation was found between minimal FMUP CV and age (r = -0.27, ns). Individual FMUP CV dispersion presented a statistically significant decrease with age (r = -0.46, P < 0.05). Furthermore, thenar motor unit number (MUNE), estimated by the adapted multiple point stimulation method, decreased progressively with age and was statistically correlated with maximal FMUP CV (r = 0.59, P < 0.01), whereas there was no correlation with minimal FMUP CV (r = 0.34, ns). Thus, we propose that motor unit loss is progressive with age throughout life, affecting particularly the largest and fastest conducting motor units. Preferential involvement of these fibers could be responsible for the age-related changes in motor nerve CV.

Corticomotoneuronal synaptic connections in normal man: an electrophysiological study.

In order to determine the mono- or oligosynaptic character of connections between pyramidal axons and individual spinal motor neurons, we constructed peri-stimulus time histograms (PSTHs) of the firing probability of voluntarily activated single motor units (SMUs) of various upper and lower limb muscles upon slightly suprathreshold transcranial anodal electrical stimulations of the motor cortex in normal subjects. Weak anodal cortical stimuli are known to activate preferentially fast-conducting pyramidal axons directly, bypassing cell bodies and cortical interneurons. A narrow bin width (0.1 ms) was chosen to measure precisely the duration of the PSTH excitatory peak, which corresponds to the rise time of the underlying compound excitatory post-synaptic potentials (EPSP). A short duration PSTH peak indicates sharp-rising EPSPs, most commonly encountered in the case of monosynaptic connections. In flexor carpi radialis and soleus SMUs, the PSTHs of built-in responses to anodal cortical stimuli were compared with those produced by 1A afferent stimulation able to elicit a Hoffmann reflex, which is known to be largely monosynaptic. In all upper and lower limb muscles, excitable SMUs responded to anodal cortical stimuli with a highly synchronized peak of increased firing probability. In flexor carpi radialis and soleus SMUs, the mean duration of this peak was significantly narrower than that evoked by 1A afferent stimulation, indicating that monosynaptic corticomotor neuronal transmission dominates low-threshold motor units, even in proximal arm and leg muscles. In the various muscles studied, and particularly in forearm SMUs, we did not observe broad PSTH peaks against the activation of non-monosynaptic corticomotor neuronal pathways, even with near-threshold stimuli. In some triceps and forearm flexor SMUs, subthreshold anodal pulses caused significant inhibition of their voluntary firing, with a latency consistent with activation of 1A inhibitory interneurons by the descending volleys. Measurements of the maximal number of counts in the excitatory PSTH peak upon anodal cortical stimuli provide comparisons of the strength of monosynaptic inputs to various muscles which seems to be maximal for hand and finger extensor muscles, and also for deltoid.

Motor and somatosensory evoked potentials in cervical spondylotic myelopathy.

We recorded upper and lower limb MEPs and SEPs in 55 patients with clinically suggestive and myelography-documented cervical cord compression due to spondylotic changes. MEPs were abnormal in biceps brachii of 21 patients (38%), in first dorsal interosseous muscle of the hand of 49 patients (89%) and in tibialis anterior of 47 patients (85%). Overall, MEP abnormalities were present in at least one muscle of 51/55 patients (93%). Median SEPs were abnormal in 20 cases (36%), ulnar SEPs in 24 (44%) and posterior tibial SEPs in 40 (73%). Overall incidence of SEP alterations was 73% (40/55) and SEPs detected clinically silent sensory dysfunction in 10 patients (18%). Among the 43 patients who underwent surgical decompression, first dorsal interosseous (FDI) MEPs and tibial SEPs remained abnormal in most cases 1 year after surgery, independently of clinical outcome. On the other hand, serial EP studies seemed useful to confirm and monitor the clinical evolution of unoperated patients.

Number and relative size of thenar motor units in ALS patients: application of the adapted multiple point stimulation method.

In the present study, the adapted multiple point stimulation (AMPS) method was first applied to median innervated thenar muscles in 22 amyotrophic lateral sclerosis (ALS) patients who did not received any treatment. In all patients, a motor unit number estimate (MUNE) and an average surface-recorded motor unit action potential (S-MUAP) size have been derived even if the denervation was severe; and the results were reproducible. The thenar MUNE was less than the normal lower limit for age in 17 patients, and the mean MUNE (67.1 +/- 90.6) was significantly different from that estimated in control subjects (263.3 +/- 116.8). The mean S-MUAP size in the 22 ALS patients was 352.9 +/- 328.4 microV x ms versus 94.1 +/- 30.3 microV x ms in healthy volunteers. A control AMPS was achieved in 8 patients after 2 and 6 months of a glutamate-release antagonist (riluzole) treatment. The mean loss of motor units, based on control thenar MUNEs realized after 6 months of treatment, was 53%. In conclusion, we propose AMPS as a manageable, reproducible and non-invasive procedure which permits one to quantify peripheral denervation and to appreciate the effectiveness of collateral reinnervation in ALS patients.

Inhibition of the blink reflex R2 component after supraorbital and index finger stimulations is reduced in cluster headache: an indication for both segmental and suprasegmental dysfunction?

Peripheral as well as central mechanisms are thought to play a role in cluster headache pathogenesis. We have studied recovery curves of the R2 component of the blink reflex after conditioning by supraorbital or index finger stimuli in 10 episodic cluster headache (CH) patients during a cluster period and in 10 healthy controls. There was no significant change of R2 threshold, latency or area in CH patients. After paired supraorbital stimuli, R2 recovered more rapidly in patients on the symptomatic side. After index stimulations, R2 recovery was more rapid on both symptomatic and non-symptomatic sides in patients compared to controls. Naloxone (0.4 mg) i.v. in two subjects partially reversed the R2 suppression induced by index finger stimuli. The unilateral decrease of R2 inhibition after a segmental supraorbital stimulus most likely reflects sensitisation in the spinal trigeminal nucleus. Whether the latter is due to irritation of the ophthalmic nerve within the cavernous sinus region, which is thought to be pivotal in CH pathogenesis, remains to be proven. In addition, we propose that the bilateral deficit of R2 inhibition after an extrasegmental exteroceptive stimulus might reflect hypoactivity of reticular nuclei, possibly because of reduced central opioid activity.

Functional changes of brainstem reflexes in Parkinson's disease. Conditioning of the blink reflex R2 component by paired and index finger stimulation.

Recovery curves of the R2 component of the blink reflex have been studied in 10 control subjects and 13 parkinsonian patients both after ipsilateral paired stimulation of the supraorbital nerve and after index finger stimulation. In control subjects, both types of conditioning induced a comparable marked inhibition lasting more than 600 ms. In parkinsonian patients, inhibition was reduced after both conditionings. However, differences appeared in the magnitude of the changes: after paired stimulation, it was less significant (ANOVA and post-hoc Duncan's test: p = 0.04) than after index finger stimulation (p = 0.002). In that latter situation, the more marked reduction in inhibition is interpreted, in the light of current physiologic knowledge, by hypoactivity of the Nucleus Reticularis Giganto Cellularis (NRGC) which would make less efficient inhibitory interneurones in the trigemino-facial pathway. The results are thus compatible with the suggestion that NRGC is made indirectly less active in Parkinson's disease.

Can motor recovery in stroke patients be predicted by early transcranial magnetic stimulation?

BACKGROUND AND PURPOSE: We used transcranial magnetic stimulation of the motor cortex to evaluate the functional state of corticospinal pathways innervating the first dorsal interosseous muscle of the hand in 26 patients suffering from a first-ever ischemic stroke in the middle cerebral artery territory. METHODS: All patients had complete hand palsy and were tested within the first 24 hours from stroke onset. Patients were also tested clinically with the MRC, Rankin, and National Institutes of Health (NIH) stroke scales at day 1 and with MRC and NIH scales and the Barthel Index at day 14. Electrophysiological testing was repeated at day 14. Patients were divided into three subgroups according to the amplitude of the maximal response (motor evoked potential [MEP]) evoked at day 1. RESULTS: After 2 weeks, all 6 patients with initial MEPs > 5% maximum motor response (Mmax) showed some first dorsal interosseous muscle motor function recovery, whereas 19 of 20 patients with initially absent or small (< 5% Mmax) MEPs were left with complete hand palsy. There were strong positive correlations between MEP amplitude at day 1 and MRC and Barthel Index scores at day 14. However, measurement of central motor conduction time proved to be of little prognostic value. CONCLUSIONS: We conclude that early-performed transcranial magnetic stimulation is a valuable prognostic tool for motor recovery from stroke and that relatively preserved MEP amplitude shortly after stroke is a better prognostic factor than normal central motor conduction time.

Intraoperative localisation of the primary motor cortex using single electrical stimuli.

A new method of intraoperative localisation of the primary motor cortex is described, based on the application of single anodal electric pulses to the brain surface. Patients were anaesthetised with propofol infusion, and neuromuscular blockade was temporarily alleviated to allow recording of surface EMG responses (CMAPs) to the stimuli. Primary motor areas could be localised in 18/19 patients studied. In the other patient, no responses were elicited, as the operative field was posterior to the motor cortex. When compared with MEPs elicited in awake patients by magnetic stimuli, responses to intraoperative anodal stimulation were of small amplitude (usually less than 10% of MEPs) and their latency was some 1 to 2 ms longer. One month after the operation, only 1/19 patients was left with a slight muscle weakness, although seven showed preoperative motor deficit. The procedure proved easy and fast, needing no preliminary surgery or time consuming preparation. It did not induce any detectable side effects.