Lorazepam-induced effects on silent period and corticomotor excitability.

TMS studies on the CNS effects of benzodiazepines have provided contradictory results. The objective of this study is to describe the effects of lorazepam on silent period (SP) and corticomotor excitability. Twelve healthy male subjects (median age 35 years) were studied at baseline, following i.v. lorazepam administration and after reversal of the benzodiazepine effects with i.v. flumazenil. Lorazepam was given at a low-dose in one subject (0.0225 mg/kg bolus + 2 microg/kg/h infusion) and at a high-dose (0.045 mg/kg bolus + 2.6 microg/kg/h infusion) in the rest. Threshold (Thr) was measured at 1% steps. SPs were investigated with two complementary methods. First, SPs were elicited using a wide range of stimulus intensities (SIs) (from 5 to 100% maximum SI at 5% increments). At each SI, four SPs were obtained and the average value of SP duration was used to construct a stimulus/response (S/R) curve of SI versus SP .The resulting S/R curves were then fitted to a Boltzman function, the best-fit values of which were statistically compared for each experimental condition (i.e., baseline vs. lorazepam vs. flumazenil). Second, a large number of SPs (n=100) was elicited during each of the three experimental conditions using blocks of four stimuli with an intensity alternating between MT and 200% MT. This method was employed so as to reveal the dynamic, time-varying effects of lorazepam and flumazenil on SP duration at two stimulus intensity (SI) levels. MEP recruitment curves were constructed at rest and during activation and fitted to a Boltzman function the best-fit values of which were statistically compared for each experimental condition. Lorazepam at a low dose did not affect Thr, SP, or the active MEP recruitment curves. The high dose also had no effect on Thr and the active MEPs whereas the resting MEP recruitment curves were depressed post-lorazepam at the higher range of stimulus intensities. With regard to SP, the Max value of the S/R curve decreased from 251+/-4.6 ms at baseline to 215.2+/-3.1 ms post-lorazepam (P<0.01). V50 also decreased significantly (from 47.92+/-0.9% to 43.73+/-0.81%, P<0.01) whereas there was no significant change regarding slope and SP Thr. The statistical analysis of the SP S/R curves as well as the study of SPs at two SI levels revealed that lorazepam reduced SP duration when high intensity stimuli were used (>60%). In contrast, at low SIs a small increase in SP duration was noted post-drug. Enhancement of GABAergic inhibition by lorazepam results in a reduction of SP duration when high SIs is used. At the lower range of SIs, a small but statistically significant increase in SP duration is observed. The kinetic behavior of this phenomenon as well as the possible underlying mechanisms are discussed.

Predicting response to treatment in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To discover whether Inflammatory Neuropathy Cause and Treatment Group (INCAT) electrophysiological criteria for demyelinating neuropathy predict response to immunotherapy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: This was a retrospective case note study of patients who had attended Guy's Hospital Peripheral Nerve Clinic between January 2001 and March 2004, been diagnosed as having CIDP, and given treatment with corticosteroids, intravenous immunoglobulin (IVIg), or plasma exchange (PE). Patients' nerve conduction studies (NCS) were reviewed for evidence of demyelination and whether the abnormalities fulfilled modified INCAT electrophysiological criteria. Patients whose NCS fulfilled the criteria were assigned to the neurophysiologically definite CIDP group, while those that did not were labelled as neurophysiologically probable CIDP. Responses to any of the three immunotherapy agents were compared between the two groups. RESULTS: Out of 50 patients, 27 (54%) were classified as neurophysiologically definite and 23 (46%) as neurophysiologically probable CIDP patients. Twenty (74%) neurophysiologically definite and 17 (73.9%) neurophysiologically probable CIDP patients responded to treatment. CONCLUSIONS: INCAT electrophysiological criteria did not predict a higher rate of response to immunotherapy. Neurophysiologically probable CIDP patients should be given a trial of immunotherapy.

The use of transcranial magnetic stimulation in the clinical evaluation of suspected myelopathy.

Central motor conduction time (CMCT) and motor evoked potential (MEP) latencies measured by using transcranial magnetic stimulation (TMS) are parameters used to evaluate electrophysiologic function of the corticospinal motor tract. We present 5 cases to illustrate how the use of TMS had contributed to clinical management. CMCT and MEP latency measurements were found to be useful in determining the significance of lesions seen on neuroimaging and helped clinical decisions in the presence of multiple lesions or multiple clinical conditions that cause similar clinical manifestations. TMS study is particularly useful in localizing levels of conduction defect.

Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS.

BACKGROUND: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABA(A) receptor, and (11)C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms. METHODS: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. (11)C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical (11)C-flumazenil binding that might explain differences in cortical excitability seen using TMS. RESULTS: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical (11)C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS. CONCLUSIONS: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. (11)C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.

Motor control of rapid sequential finger tapping in humans.

We investigated in 29 healthy subjects a simple model of rapid independent finger movement: the rapid sequential tapping of adjacent fingers. Inter-tap interval (ITI) was measured for adjacent pairs of fingers in each direction. ITI was shorter in the ulnar-->radial direction than in the reverse direction [P < 0.001 for middle to index (M-->I) compared with index to middle (I-->M)]. There was a gradient across the hand such that in the ulnar-->radial direction, little to ring (L-->R) tapping was fastest and M-->I slowest; in the radial-->ulnar direction, the reverse was the case. Rectified surface electromyography (EMG) from finger extensors and flexors was averaged with respect to either the first or second tap. The interval between the flexor EMG burst and the tap was similar irrespective of the order of finger tapping, excluding a mechanical explanation of the timing difference. Transcranial magnetic stimulation (TMS) was applied at 0- to 50-ms intervals after the first tap. Interposed TMS delayed the second tap significantly more (P < 0.001) in the M-->I direction than in the I-->M direction. Motor-evoked potentials (MEPs) evoked by TMS interposed between taps showed a greater facilitation in the M-->I than in the I-->M direction (P < 0.001). Increasing intensity of TMS rendered subjects unable to produce the second tap, more frequently in the I-->M direction than in the M-->I direction. We have demonstrated a consistent pattern across the hand and postulate that finger-order-dependent differences in ITI and the gradient of these across the hand may reflect the mechanism of grasping and further that the cortical programming of finger tapping differs depending on finger order.

Silent period to transcranial magnetic stimulation: construction and properties of stimulus-response curves in healthy volunteers.

Silent period (SP) is widely used in transcranial magnetic stimulation studies. Methodologically, SP is usually elicited at stimulus intensities corresponding to a certain percentage of corticomotor threshold. Because this approach might lead to factitious SP changes, the present study was designed to develop, in a stepwise manner, a method for investigating SP independently of corticomotor threshold. First, stimulus-response (S-R) curves of SP against stimulus intensity (SI) were constructed and quantitatively described in healthy volunteers. Second, various methodological issues such as the optimum model for describing the relationship between SP duration and SI and the importance of the type of stimulating coil were addressed. Finally, the proposed method and a commonly used method (eliciting SPs at 130% MT SI) were directly compared for a group of epileptic patients for whom administration of oxcarbazepine resulted in significant corticomotor threshold elevation. Twenty-one subjects (eleven females, median age, 38 years) were studied. SPs were obtained with a figure-of-eight coil using a standardized procedure (recording, FDI). Pilot experiments indicated that at least four trials were required, at each intensity level, to estimate the mean SP duration within 10% of the true mean. Therefore, SPs were determined from the average of four trials with 5% increments from 5 to 100% maximum SI. In a second set of experiments, SPs were obtained for fifteen subjects using a circular coil. In a third set of experiments, eight epileptic patients were studied before and after administration of oxcarbazepine (mean dose 1553 mg, range 900-1800 mg). The S-R curves were fitted to a Boltzman function and to first-order to fourth-order polynomial and sigmoid functions. The Boltzman function described the data accurately (R2=0.947-0.990). In addition, direct comparison of the six models with an F-test proved the superiority of the first. The best-fit parameters of the reference curve, i.e. the maximum and minimum values, the slope, and V50 (the SI at which SP duration is halfway between Min and Max) were 230.8+/-3.31 ms (x+/-SEM), -11.51+/-3.31 ms, 11.56+/-0.65%, and 49.82+/-0.65%, respectively. When the curves obtained with the circular coil were compared with those obtained with the figure-of-eight coil, there were differences between V50 (51.69+/-0.72 vs 47.95+/-0.82, P<0.001) and SP threshold (31.15 vs 24.77, P<0.01) whereas the other best-fit values did not differ significantly. Oxcarbazepine increased corticomotor threshold from 45.3+/-5.8% at baseline to 59.4+/-10.4% (P<0.001). According to the commonly used method, the drug significantly prolonged SP (from 117.6+/-42.4 ms to 143.5+/-46.5 ms, P<0.001) and, consequently, enhanced brain inhibition. In contrast, study of the SP curves led to the conclusion that oxcarbazepine does not affect the Max value and slope but significantly increases V50 and SP threshold (from 54.5+/-4.9% to 59.9+/-7.2% and from 29.1+/-6.4% to 34.6+/-6.8%, respectively, P<0.01). These findings imply that oxcarbazepine does not enhance brain inhibitory mechanisms. Thus, in situations characterized by significant changes in corticomotor threshold the proposed method provides results clearly different from a commonly used approach. It is concluded that S-R curves obtained with a figure-of-eight coil in 5% increments and fitted to a Boltzman function provide an accurate, comprehensive, and clinically applicable method for exploring SP.

The repeatability of corticomotor threshold measurements.

Threshold (Th) is a neurophysiological parameter frequently used in TMS studies. The present study was designed to investigate the repeatability of the Th measurements by reexamining healthy subjects over various time points. Overall, 82 subjects (median age: 19 years, range: 12-65) entered the study. Following a baseline examination, there were six retest sessions: S0 (n = 8 hemispheres reexamined, mean interval x = 19 min), S1 (n = 34 hemispheres reexamined, mean interval x = 4 days), S2 (n = 32 hemispheres, x = 29 days), S3 (n = 30 hemispheres, x = 106 days), S4 (n = 30 hemispheres, x = 183 days) and S5 (n = 30 hemispheres, x = 1867 days). Stimulation was performed with a figure of eight coil and Th was defined at 1% steps. At baseline, controls had an MT of 41.1 +/- 8. Mean difference of MT from baseline was 0.62 on S0 (95% confidence interval (CI) of the difference: -1.04 to +2.29), 0.13 on S1 (95% CI: -1.2 to +1.5), -0.03 on S2 (95% CI: -1.1 to +1.06), -2.07 on S3 (95% CI: -4.33 to +0.19), 0.15 on S4 (95% CI: -0.98 to +1.28) and 0.87 on S5 (95% CI: -0.49 to +2.23). None of these differences were statistically significant (repeated measures ANOVA, P > 0.05). The upper limit of MT difference that an individual subject might have with a probability of 95% (measurement error) was 8. The repeatability of the method was found to be independent from the age of the subjects, the magnitude of threshold or the test-retest interval. The topography of corticomotor threshold was also investigated. Minimal threshold values were obtained from a restricted area of scalp sites that always included the fixed stimulation point of the current protocol. Therefore, using a fixed stimulation point is an adequate technique for measuring threshold. In conclusion, threshold is a stable parameter on an individual and group basis. These data quantify the repeatability of the method and may prove useful in the interpretation of findings during longitudinal studies.

The natural history of central motor abnormalities in amyotrophic lateral sclerosis.

Degeneration of spinal motoneurons has been well documented in amyotrophic lateral sclerosis (ALS), but the evolution of central motor abnormalities is largely unknown. It has been suggested that glutamate-mediated neuroexcitotoxicity may be involved in the pathogenesis of ALS and that this may be manifest as an increase in corticomotor excitability early in the disease. Serial measurements of corticomotor threshold, central motor conduction time (CMCT), silent period duration and the amplitude of compound muscle action potentials (CMAPs) from ulnar nerve stimulation in the right and left first dorsal interosseous muscles were made in 76 patients with idiopathic ALS, 49 of whom were followed from presentation to death. Threshold to transcranial magnetic stimulation was determined by standard methods and CMCT was measured using the F-wave method. Silent period was estimated during a small background contraction of the muscle. Patients were classified according to the region of onset and the physical signs in the hands. The region of onset was bulbar in 17 patients, lower limb in 31 patients and upper limb in 28 patients. At presentation, 23 patients had no abnormal physical signs in the hands, 25 had lower motoneuron signs only, 14 had upper motoneuron signs only and the remainder (14) had mixed upper and lower motoneuron signs in the hands. Evolution of the central conduction parameters was determined in relation to time from onset of symptoms and also as a function of normalized total disease duration in the patients who had died. Corticomotor threshold and CMCT showed no change as the disease evolved except for patients with mixed signs, who had a terminal increase in threshold and prolongation of CMCT. Silent period duration was shorter than normal early in the disease and showed progressive lengthening throughout the illness, but nevertheless remained within the normal range regardless of the region of onset. CMAP amplitude showed a linear decline over the course of the disease. There was therefore no evidence of a phase of increased corticomotor hyperexcitability at any stage of disease progression. The early shortening of silent period, however, probably represents a shift in the balance of excitatory and inhibitory inputs to the cortical output cells responsible for voluntary action, and could be a reflection of degeneration of cortical interneurons. None of the measures of central motor function in ALS are likely to be useful for monitoring patients in a clinical trial setting.

Transcutaneous cervical root stimulation in the diagnosis of multifocal motor neuropathy with conduction block.

OBJECTIVES: To determine if transcutaneous electrical stimulation of the cervical roots can be used to diagnose proximal conduction block (CB) in multifocal motor neuropathy (MMN) and whether it can reliably distinguish MMN from amyotrophic lateral sclerosis (ALS). METHODS: Compound muscle action potentials (CMAPs) over the abductor digiti minimi (ADM) were evoked by supramaximal stimulation of the ulnar nerve at the wrist, below elbow, above elbow, axilla, Erb's point, and C8/T1 cervical roots in three groups of patients: 31 patients with ALS, nine patients with MMN, and 31 controls. Supramaximal stimulation at Erb's point and the C8/T1 roots was carried out using a transcutaneous high voltage electrical stimulator. The negative peak amplitude, area, and duration of the CMAP were measured and normalised to that from the wrist. The percentage change in each segment in these parameters was calculated and compared between the different groups. RESULTS: At stimulation sites proximal to the elbow, there were no significant differences in relative CMAP amplitude, area, or duration between controls, ALS patients, and MMN patients with clinically unaffected ulnar nerves. Similarly, the percentage segmental change between adjacent stimulation sites showed no significant differences. In six studies of MMN patients with weakness in ulnar hand muscles, the decrease in CMAP amplitude between the C8/T1 roots and Erb's point exceeded the mean + 2 SD of the control data. CONCLUSION: Cervical root stimulation can quantify CB in the most proximal segment of the ulnar nerve, a fall in CMAP amplitude if greater than 25%, indicating block, and should be used routinely in the evaluation of patients suspected of having MMN, especially when distal stimulation has proved unhelpful.

Mapping motor cortex projections to single motor units in humans with transcranial magnetic stimulation.

We devised a method to investigate the cortical organization of corticomotoneurons (CMs) to upper limb muscles. A spike-triggering technique was used, in which a tonically discharging single motor unit (SMU) triggered transcranial magnetic stimulation (TMS) of motor cortex, and the probability of producing short-latency discharges (primary excitatory responses [PERs]) was measured. PER probabilities were mapped in 34 SMUs, using a 16 cm(2) scalp grid with the central reference point having a probability of 0.5. Maps showed a single optimum point of scalp stimulation and significant decreases in PER probability with shifts of 2 cm from this point, for all subjects. These findings suggest that the colony of CMs projecting to an individual SMN is contained within a small volume of motor cortex. Changes in PER probability with shifts in stimulation site may reflect the organization of other intracortical neurons mediating TMS activation of these CMs.

Further evidence for corticomotor hyperexcitability in amyotrophic lateral sclerosis.

A collision experiment has been used to investigate repetitive firing of first dorsal interosseous motoneurons following a single transcranial magnetic stimulus (TMS) in healthy subjects and patients with amyotrophic lateral sclerosis (ALS). An appropriately timed supramaximal peripheral nerve shock blocks the first descending impulses in the motor axons and allows the response due to repetitive firing to be quantified. Multiple firing of motoneurons in healthy subjects increases as TMS intensity rises and saturates at about 1.25 times threshold. Increasing background force also augments repetitive firing and saturates at force levels above 50% maximum. The ratio of the area of the response attributed to repetitive motoneuron firing to the area of the initial direct response to TMS was compared in 10 ALS patients and 10 healthy controls. In ALS patients, the ratio was significantly higher (P = 0. 0005), indicating a greater degree of repetitive firing of motoneurons. This suggests that, in ALS, there is corticomotor hyperexcitability either at the spinal motoneuron or motor cortex.

Clinical, electrophysiological, and molecular genetic studies in a new family with paramyotonia congenita.

OBJECTIVES: To characterise the clinical and electrophysiological features and to determine the molecular genetic basis of pure paramyotonia congenita in a previously unreported large Irish kindred. METHODS: Clinical and neurophysiological examination was performed on three of the five affected family members. Five unaffected and three affected members of the family were available for genetic testing. Direct sequence analysis of the SCN4A gene on chromosome 17q, was performed on the proband's DNA. Restriction fragment length polymorphism (RFLP) analysis was used to screen other family members and control chromosomes for the SCN4A mutation identified. RESULTS: Each affected member had clinical and examination features consistent with pure paramyotonia congenita. Electrophysiological studies disclosed a 78% drop in compound muscle action potential (CMAP) amplitude on cooling to 20 degrees C. DNA sequence analysis identified a heterozygous point mutation G4367A in exon 24 of the SCN4A gene which segregated with paramyotonia and was absent in 200 control chromosomes. The mutation is predicted to result in a radical amino acid substitution at a highly conserved position within the voltage sensing fourth transmembrane segment of the fourth repeated domain of the sodium channel. CONCLUSIONS: The G4367A mutation is likely to be pathogenic and it associates with a pure paramyotonia phenotype. In keeping with other paramyotonia mutations in this region of the skeletal muscle sodium channel, it is predicted that this mutation will impair voltage sensing or sodium channel fast inactivation in a temperature dependent fashion. This study provides further evidence that exon 24 in SCN4A is a hot spot for paramyotonia mutations and this has implications for a DNA based diagnostic service.

Axonal injury or loss in the internal capsule and motor impairment in multiple sclerosis.

OBJECTIVE: To test the hypothesis that axonal damage extending into primarily normal-appearing white matter is clinically important by comparing the concentrations of N-acetylaspartate (NAA) bilaterally within the internal capsule with lateralization of motor impairment in patients with multiple sclerosis (MS) and persistent asymmetrical motor deficit. DESIGN: We performed magnetic resonance spectroscopy and T2-weighted imaging of the internal capsule, calculated central motor conduction times, and related these results to measures of motor function asymmetry in 12 patients with MS. RESULTS: Levels of NAA from normal-appearing white matter of the internal capsule in patients with MS were significantly lower than those in control subjects (P = .05). Side-to-side differences in NAA levels were also significantly greater in patients with MS than in controls (P = .01). There was a correlation between asymmetry in motor function for the left and right limbs and asymmetry of internal capsule NAA concentrations (r = 0.60; P = .04). This correlation seemed slightly stronger when tests specifically of arm and hand motor asymmetry were considered alone. Central motor conduction times were abnormal in most patients with MS and showed a side-to-side difference that also correlated with asymmetry in motor function. CONCLUSION: Our demonstration of a graded association between NAA concentrations within primarily normal-appearing white matter of a specific tract and functional impairments referable to that tract suggests that axonal pathology distant from macroscopic lesions might be an important determinant of disability in MS.

Do the same genes predispose to Gilles de la Tourette syndrome and dystonia? Report of a new family and review of the literature.

Gilles de la Tourette syndrome (TS) and idiopathic focal torsion dystonia are both movement disorders in which the pathologic process is thought to arise within the basal ganglia. However, despite their possible functional links, they are clinically distinct and are generally considered to have different underlying etiologies. There are several reports in the literature that suggest a relationship between eye winking tics, excessive blinking, and blepharospasm and a report of the coexistence of tics and dystonia. We describe a three-generation family in which TS and dystonias cosegregate. In total, eight patients were affected, five with dystonia and three with TS/facial tics. One of the patients with historic evidence of dystonia subsequently died of motor neuron disease. The identification of this family further strengthens the evidence in favor of an etiologic relationship between some cases of Gilles de la Tourette syndrome and focal dystonia.

Strength-duration properties of peripheral nerve in acquired neuromyotonia.

The strength-duration time constant (SDTC) of a myelinated axon is a property of the nodal membrane and is sensitive to changes in membrane potential. Strength-duration time constants for motor axons and cutaneous afferents of the median nerve were measured in 9 patients with acquired neuromyotonia (NMT), a condition of peripheral nerve hyperexcitability, and 15 control patients. Mean motor axon time constants were significantly prolonged (344 +/- 100 micros) in patients compared to healthy controls (264 +/- 34 micros; P = 0.038), but sensory axon time constants were not significantly different. Motor axon time constants were longer than sensory axon time constants in 4 of the patients with neuromyotonia, suggesting that the nodal membrane was depolarized by an ectopic focus at the site of nerve stimulation at the wrist, ionic conductances were altered at the node, or that the size of the node was increased, possibly as a result of immune-mediated damage. The anti-voltage-gated potassium channel antibodies thought to generate peripheral nerve hyperexcitability in acquired neuromyotonia may be indirectly responsible for changes in motor axon nodal membrane properties.