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.     

Cortical excitability in patients with essential tremor

We used transcranial magnetic stimulation in 10 patients with essential tremor and 8 matched healthy subjects. A round stimulating coil was placed over the vertex and electromyographic activity was recorded from the first dorsal interosseous muscle. Paired transcranial stimuli were delivered at interstimulus intervals of 3, 5, 20, 100, 150, and 200 ms. The intensity of the conditioning stimulus was 80% of motor threshold at short and 150% at long interstimulus intervals (ISIs). We also measured the silent period obtained after a single magnetic pulse delivered at 150% of motor threshold during a submaximal muscle contraction. Patients and controls had similar motor threshold and similar latencies. Paired magnetic stimuli given at short and long ISIs at rest, and during a voluntary muscle contraction, elicited similar responses in both groups. The silent period evoked by transcranial magnetic stimulation had a similar duration in patients with ET and controls. In conclusion, these findings suggest that patients with essential tremor have normal cortical motor area excitability.     

The cellular localization of 5-HT2A receptors in the spinal cord and spinal ganglia of the adult rat

Cortical inhibitory mechanisms were investigated with the technique of paired transcranial magnetic stimulation in 10 patients with dystonia of the right arm: six patients had focal, task-specific dystonia (writer's cramp) and three had segmental and one had generalized dystonia. Paired stimuli were delivered in a conditioning-test design during slight voluntary activation of the target muscle, with subthreshold conditioning stimuli at short intervals (3-20 ms) and suprathreshold conditioning stimuli at long intervals (100-250 ms). The amount of inhibition at short interstimulus intervals did not differ significantly between patients and normal subjects. With long interstimulus intervals, patients showed more inhibition of the test response, which was significant at the 150-ms interval. The cortical silent period following a single suprathreshold magnetic stimulus was slightly shorter in patients. No significant difference was detected between the affected side and the unaffected side in patients with unilateral task-specific dystonia, neither in the duration of the silent period nor in the response to paired magnetic stimuli. These results indicate that the different types of motor cortical inhibition are produced by different inhibitory circuits. We propose that the alterations observed in patients with dystonia are the result of impaired feedback from the basal ganglia to motor cortical areas, with the ultimate effect of a flattening of the excitability curve of the cortical motoneuron pool during voluntary muscle activation.     

Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation

We investigated 14 patients with amyotrophic lateral sclerosis (ALS) by paired conditioning-test transcranial magnetic stimulation to test the hypothesis that the motor cortex is hyperexcitable in ALS. Intracortical (corticocortical) inhibition was significantly less in the ALS group than in an age-matched healthy control group (85.3 +/- 27.0% versus 45.2 +/- 15.5%, respectively; p < 0.0001). In contrast, intracortical facilitation, motor threshold, and cortical silent period duration in the ALS patients were not different from the control group. We suggest that the selective abnormality of intracortical inhibition is best compatible with an impaired function of inhibitory interneuronal circuits in the motor cortex that in turn renders the corticomotoneuron hyperexcitable.     

Spindle frequency activity in the sleep EEG: individual differences and topographic distribution

Focal magnetic transcranial stimulation (TCS) is employed for mapping of the motor cortical output to abductor digiti minimi (ADM) muscle. The aim of this study was to evaluate the interhemispheric asymmetries in normals. Motor maps were obtained through motor evoked potentials (MEPs) recordings from ADM muscle in 20 healthy subjects in right and left hemispheres TCS. Measurement of several indexes such as excitability threshold, MEPs amplitude, MEPs latency, and silent period duration did not show differences between the hemispheres. Moreover, no interhemispheric asymmetries were found when the amplitude ratio values were analyzed. The hand motor cortical area, as represented by the number of responsive sites (3.6 vs. 3.5) and the "hot spot" site localization presented a fairly symmetrical organization. Absolute values displayed a relatively wide intersubject variability, while their interhemispheric differences were extremely restricted. This observation can offer a new tool in diagnosing and following up neurological disorders affecting the central motor system, mainly for those concerning monohemispheric lesions.     

Isolated trochlear nerve palsy caused by mixed dural-pial arteriovenous malformation of the anterior cranial fossa: a case report

The present study makes use of the photic induction of Fos in the suprachiasmatic nucleus (SCN) to explore the pharmacology of retinal input to this circadian pacemaker. Our results demonstrate that the GABAA antagonist bicuculline and the benzodiazepine agonist diazepam, both of which prevent light-induced phase shifts, do not inhibit photic induction of Fos expression in the hamster SCN. In contrast, the GABAB agonist, baclofen, prevents both light-induced phase shifts and inhibits photic induction of Fos expression in the SCN. One explanation of this difference may be that baclofen acts to prevent photic information from reaching the SCN while bicuculline and diazepam act within the SCN at a point 'downstream' from Fos induction.     

Cortical hyperexcitability in progressive myoclonus epilepsy: a study with transcranial magnetic stimulation

In progressive myoclonus epilepsy (PME), responses to afferent input are frequently abnormal. It is unclear whether the abnormality lies at the cortical, subcortical, or segmental level. To obtain evidence for an exaggerated effect on motor cortical excitability, we used peripheral nerve and transcranial magnetic stimulation in controls and subjects with idiopathic generalized epilepsy and PME. Mean threshold intensity was higher in those with idiopathic generalized epilepsy and PME than in controls, probably as a result of anticonvulsant treatment. A long-latency response to peripheral stimulation and an exaggerated facilitatory effect of peripheral stimulation on the motor evoked potential was present in subjects with PME. Latency differences between the late responses in the upper and lower limbs provided evidence against a segmental reflex and implicated rapidly conducting fibers in the spinal cord. Both the late response and the facilitatory effect had onset latencies consistent with a transcortical pathway, suggesting an exaggerated effect of afferent input on motor cortical excitability in PME.     

Anonymity and pseudonymity in whistleblowing to the U.S. Office of Research Integrity

This study attempts to find out whether the motor evoked potential (MEP) elicited by single pulse and slow-rate (1 Hz) repetitive transcranial magnetic stimulation (TMS) can disclose concealed subclinical impairments in the cerebral motor system of patients with minor head injury. The motor response to single pulse TMS (STMS) of the patient group was characterized by significantly higher threshold compared with that of the control group. The central motor conduction time, as well as the peripheral conduction time were normal in all patients pointing to cortical impairment. Two main patterns of MEP changes in response to repetitive TMS (RTMS) were observed in the patient group. A.--progressive decrease of the MEP amplitude throughout the stimulation session to a near complete abolition. B.--irregularity of the amplitude and the waveform of the MEP in a chaotic form. The MEP latency remained stable during the whole stimulation session. The MEP abnormalities recovered gradually over the period of a few months. The higher threshold of the motor response to STMS and the abnormal patterns of the MEP to RTMS seem to reflect transient impairment of cortical excitability or "cortical fatigue" in patients who sustained minor head injures. Further study is needed to evaluated the extent and the pathophysiological mechanisms of the central nervous system fatigue phenomenon following head injury.     

Amino-terminal identity of co-existent amyloid and non-amyloid immunoglobulin kappa light chain deposits. A human disease to study alterations of protein conformation

The sizes of the motor-evoked potentials (MEPs) and the durations of the silent periods after transcranial magnetic stimulation were examined in biceps brachii, brachioradialis and adductor pollicis in human subjects. Stimuli of a wide range of intensities were given during voluntary contractions producing 0-75% of maximal force (maximal voluntary contraction, MVC). In adductor pollicis, MEPs increased in size with stimulus intensity and with weak voluntary contractions (5% MVC), but did not grow larger with stronger contractions. In the elbow flexors, MEPs grew little with stimulus intensity, but increased in size with contractions of up to 50% of maximal. In contrast, the duration of the silent period showed similar changes in the three muscles. In each muscle it increased with stimulus intensity but was unaffected by changes in contraction strength. Comparison of the responses evoked in biceps brachii by focal stimulation over the contralateral motor cortex with those evoked by stimulation with a round magnetic coil over the vertex suggests an excitatory contribution from the ipsilateral cortex during strong voluntary contractions.     

A case of cortical reflex positive-negative myoclonus--electrophysiological study

An 11-year-old girl who had the positive-negative myoclonus and the history of the generalized tonic clonic seizure was electrophysiologically studied. She had no siblings with either myoclonus or epilepsy, and her intellectual level was normal. She had no other neurological deficits including ataxia, pyramidal and extrapyramidal signs. Surface EMG showed a brief increase in the EMG activity followed by the silent period associated with positive and negative myoclonus during sustained wrist extension. Giant SEP and C reflex (38.6 ms) following electric stimulation of the median nerve at the wrist were obtained in the resting condition and the silent period (about 180 ms) following C reflex was obtained during voluntary contraction. Jerk-locked back averaging of the EEG time-locked to the onset of the myoclonic discharge recorded from the right biceps muscle showed a cortical spike at the left central region preceding the myoclonus onset by 12.6 ms. The latency of C reflex in this case was very short compared with that of previously reported cortical reflex myoclonus. The estimated cortical delay between the arrival of the somatosensory volley and the motor cortex discharge responsible for the C reflex was -1.0 ms and this value was shorter than that in patients with typical cortical reflex myoclonus (mean 3.7 +/- 1.1 ms). Conditioning stimuli (C) of the right median nerve at the wrist started to facilitate the amplitude of the motor evoked potential recorded from the right abductor pollicis brevis muscle after magnetic test stimuli (T) of the left motor cortex at 20 ms of the C-T interval. This C-T interval was shorter than that (24.6 +/- 1.6 ms) in patients with the typical cortical myoclonus. These electrophysiological findings suggested the shorter reflex pathway of the cortical reflex myoclonus in this case than in typical cortical reflex myoclonus. We speculated that the myoclonus was based upon the direct sensory projection from the thalamus to the motor cortex in this case.     

Mechanisms underlying spinal motor neuron excitability during the cutaneous silent period in humans

The transient suppression of muscle contraction during the cutaneous silent period (CSP) could be produced either through postsynaptic inhibition of motoneurons or through presynaptic inhibition of the excitatory inputs to motoneurons that sustain voluntary contraction. We sought to delineate the mechanisms underlying the CSP in hand muscles by measuring changes in H-reflexes and motor-evoked potentials (MEPs) produced by transcranial magnetic stimulation (TMS) during the CSP in 10 healthy volunteers. H-reflexes and MEPs both measure the excitability of the motoneuron pool and activate similar subpopulations of motoneurons through different pathways. Inhibition of H-reflexes and MEPs of similar size was maximal at the midpoint of the CSP and gradually returned to baseline. The similar time course of recovery suggests that the H-reflex and MEP are affected by inhibition at a common site, most likely postsynaptic inhibition of the motoneurons.     

Management of caustic esophagitis in adults

We investigated whether a cortical potential exists, that is similar to the Bereitschaftspotential, preceding postural adjustment followed by voluntary ballistic rising on tiptoe in 10 healthy subjects. On the basis of the electromyogram (EMG) activities of the soleus muscle, the onsets of the premotion silent period (PMSP) and EMG discharge were determined. The negative potentials associated with a voluntary rise-on-tiptoe movement with respect to EMG onset were similar to the readiness potential associated with voluntary foot movement. The slopes of the slow negative potential associated with the PMSP onset were significantly more negative than those of the potential associated with rise-on-tiptoe movement, particularly over the frontal electrode positions. The results suggest that a cortical potential precedes postural adjustment that is followed by voluntary rising on tiptoe.     

An approach for assaying benzodiazepine receptor binding with radioiodinated ligand: 125I-labeled diazepam derivative

[125I]2'-Iododiazepam (IDZ) was prepared and its application in a benzodiazepine receptor binding assay was studied. [125I]2'-IDZ binds to the rat cortical membrane with a high affinity (Kd, 0.66 nM). Various benzodiazepines showed competition with [125I]2'-IDZ for the binding sites in the rat cortical membrane, and the specificity of its binding correlated well with that of [3H]diazepam (r = 0.992, p < 0.001). These findings suggested that [125I]2'-IDZ binds to the same sites as [3H]diazepam and indicated that [125I]2'-IDZ can be used in a benzodiazepine receptor assay.     

Dependence of the transcranially induced silent period on the 'instruction set' and the individual reaction time

OBJECTIVES AND METHODS: We looked for influences of the experimental condition on the silent period (SP) from transcranial motor cortex stimulation and analyzed how the instruction given to the subject, as well as the individual reaction time, might affect the duration of the SP in the biceps brachii muscle. RESULTS: The duration of the SP was found to critically depend on the subject's voluntary reaction of the target muscle immediately after the stimulus. With low stimulus intensity and low background force, the duration of the silent period was significantly longer in 10 of 13 subjects (P = 0.002) when they were instructed to relax quickly after the stimulus rather than to maintain the the force at a constant level. A significant shortening of the SP (P = 0.02) was observed when the subjects were instructed to perform a rapid contraction of the target muscle in reaction to the cortical stimulus. With low stimulus intensity and high background force, the same influence of the instruction set was found in 6 of 13 subjects. When the subjects were left without precise instruction, the SP duration was unpredictable. In 10 subjects, the SP corresponded to that obtained with the instruction to maintain the force at a constant level. However, in 3 subjects it was prolonged to the value observed in the 'relax' instruction. With greater stimulus intensities, the effect of the instruction set on the SP duration was generally smaller. A significant prolongation was nevertheless found at low background forces with rapid relaxation (P < 0.001), and a significant shortening was found at high background forces with rapid contraction (P < 0.001) after the stimulus. The SP duration observed with 20% of maximal voluntary contraction (MVC) significantly correlated with the individual reaction time. No such correlation was found for the SP obtained with 80% MVC. The SP was slightly longer at 20% MVC, as compared to 80% MVC within each instruction group. This effect was significant (P < 0.05) at low stimulus intensities. CONCLUSIONS: Therefore, when assessing the SP duration for diagnostic purposes, not only the stimulus intensity but also the background force and the voluntary reaction must be standardized. Furthermore, great stimulus intensities and high background forces should be used to minimise the effects of instruction set and individual reaction time.     

Variation in the masseteric silent period in older dentate humans and in denture wearers

The masseteric silent period was elicited by chin taps at 40% clenching in the masseter muscle of the preferred chewing side in 22 younger dentate individuals, in 22 older dentate individuals, in 22 older experienced denture wearers and in 7 older inexperienced denture wearers. One simple and three combined types of silent period (combination of early and late phases of depression) were recorded in all groups. An early silent period was always elicited, the only exception being in some inexperienced denture wearers. Both the age and the extent of rehabilitation with dentures in the trained denture wearers affected reflex latencies (p < 0.05), while the variation in duration was not significant (p > 0.05). The duration of the silent period was, however, affected by the type of silent period, thus by the measuring technique (p < 0.05). Increased variation was observed in the inexperienced denture wearers, who were in a period of adaptation.     

Naloxone and baclofen attenuate ethanol's locomotor-activating effects in preweanling Sprague-Dawley rats.

Heterogeneous rat strains appear to be particularly sensitive to the sedative effects of ethanol as adults and insensitive to ethanol's stimulant effects. Recently, the authors found that ethanol induces stimulant effects in preweanling Sprague-Dawley rats. In adult mice, these effects seem to be governed by the mesocorticolimbic dopaminergic pathway, which can be modulated by means of GABA B agonist (baclofen) or opioid antagonist (naloxone) treatments. This study tested whether these pharmacological treatments might reduce the activating effect of ethanol in preweanling Sprague-Dawley rats. Twelve-day-old pups given naloxone (Experiment 1A) or baclofen (Experiment 1B) before ethanol administration were tested in terms of locomotor activity in a novel environment. Naloxone and baclofen significantly reduced the stimulating effect of ethanol but had no effect on locomotor activity patterns in water-treated controls. Blood ethanol levels were not affected by naloxone or baclofen (Experiment 2). During the preweanling period, opioid and GABA B receptors seem to be involved in the stimulating effect of ethanol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

GABAergic influences on plus-maze behaviour in mice

Manipulations of GABA function have been found to produce highly variable effects in animal models of anxiety. In the present series, an ethological version of the murine elevated plus-maze was used to examine in detail the behavioural profiles of diazepam (1.5 mg/kg; positive control) and a range of GABA-related compounds: valproic acid (100-400 mg/kg), No-711 (1.25-10.0 mg/kg), muscimol (0.5-3.0 mg/kg), (+)bicuculline (4.0-8.0 mg/kg), picrotoxin (0.25-2.0 mg/kg), R(+)baclofen (0.375-3.0 mg/kg) and CGP 35348 (25-200 mg/kg). On both conventional and ethological indices, results confirmed the anxiolytic profile of diazepam under present test conditions, and revealed substantially similar effects for the GABA-T inhibitor, valproic acid (100-400 mg/kg), and the GABAA receptor agonist, muscimol (2 mg/kg). The GABA reuptake inhibitor, No-711, produced weak anxiolytic-like effects at low doses (1.25-2.5 mg/kg) but disrupted behaviour at the highest dose tested (10 mg/ kg). Although the GABAA receptor antagonists, (+)bicuculline and picrotoxin, produced changes indicative of anxiety enhancement, concomitant behavioural suppression was evident at high doses (8 mg/kg and 1-2 mg/kg, respectively). Further studies suggested that the effects observed with bicuculline may be mediated by an active metabolite, such as bicucine. In contrast to the effects of valproic acid and direct GABAA receptor manipulations, the GABAB receptor agonist, R(+) baclofen, non-specifically disrupted behaviour at the highest dose tested (3 mg/kg) while the GABAB receptor antagonist, CGP 35348, was inactive over the dose range studied. Although present data confirm the sensitivity of the plus-maze to agents which modify GABAA receptor function, further studies will be required in order more fully to characterize this relationship.     

Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity

OBJECTIVE: To investigate whether the stiff limb syndrome may be separated from the stiff man syndrome and progressive encephalomyelitis with rigidity on simple clinical grounds, and whether such a distinction has implications for aetiology, treatment, and prognosis. METHODS: Twenty three patients referred over a 10 year period with rigidity and spasms in association with continuous motor unit activity, but without evidence of neuromyotonia, extrapyramidal or pyramidal dysfunction or focal lesions of the spinal cord were reviewed. The patients were divided into those with an acute or subacute illness, leading to death within 1 year, and those with a chronic course. The latter were divided into those in whom rigidity and spasms dominated in the axial muscles, or in one or more distal limbs, at the time of their first assessment. RESULTS: This simple division identified three distinct groups of patients. (1) Progressive encephalomyelitis with rigidity: two patients had a rapidly progressive condition characterised by widespread rigidity which resulted in death within 6 and 16 weeks. One patient had negative anti-GAD and anti-neuronal antibodies, but had markedly abnormal CSF and widespread denervation. The principal pathological findings in this case were a subacute encephalomyelitis which primarily affected the grey matter. In the remaining patient anti-GAD antibodies were not tested, and postmortem was refused. (2) Stiff man syndrome: eight patients had rigidity and painful spasms of the lumbar paraspinal, abdominal, and occasionally proximal leg muscles associated with a lumbar hyperlordosis. There was no involvement of the upper limbs, distal lower limbs, sphincters or cranial nerves. Seven had anti-GAD antibodies and most had additional evidence of autoimmune disease. Neurophysiologically there was continuous motor unit activity with abnormal exteroceptive reflexes, but a normal interference pattern during spasms. The patients all responded to baclofen/diazepam and remained ambulant. (3) Stiff limb syndrome: thirteen patients had rigidity, painful spasm, and abnormal postures of the distal limb, ususphincter or brainstem involvement. Generalised myoclonic jerks were not a feature. Only two had truncal rigidity, and another two had anti-GAD antibodies. Most had no evidence of autoimmune disease. Neurophysiologically they had continuous motor unit activity in the affected limb, abnormal exteroceptive reflexes, and abnormally segmented EMG activity during spasms. The disease ran a protracted course, and most patients had only a partial response to baclofen or diazepam. About half became wheelchair bound. CONCLUSIONS: The stiff limb syndrome seems distinct from the stiff man syndrome or progressive encephalomyelitis with rigidity, and is an important cause of rigidity and spasm in the setting of continuous motor unit activity.     

Plasma diazepam concentrations following prolonged administration

Plasma diazepam and N-desmethyl diazepam concentrations were measured in patients receiving diazepam 5 mg or 10 mg i.v. at 4-h intervals for periods of 6-22 days. At both doses there was an accumulation of both diazepam and its metabolite, the latter reaching concentrations of up to two to three times that of the parent drug. Plasma diazepam concentrations reached a plateau after 8 days while the concentration of N-desmethyl metabolite continued to increase throughtout the period of drug administration. On discontinuation of diazepam therapy both diazepam and N-desmethyl diazepam concentrations decreased slowly, the former with a half-life of 2-4 days and the latter with a half-life of 4-8 days.     

Rapidly induced auditory plasticity: the ventriloquism aftereffect

Cortical representational plasticity has been well documented after peripheral and central injuries or improvements in perceptual and motor abilities. This has led to inferences that the changes in cortical representations parallel and account for the improvement in performance during the period of skill acquisition. There have also been several examples of rapidly induced changes in cortical neuronal response properties, for example, by intracortical microstimulation or by classical conditioning paradigms. This report describes similar rapidly induced changes in a cortically mediated perception in human subjects, the ventriloquism aftereffect, which presumably reflects a corresponding change in the cortical representation of acoustic space. The ventriloquism aftereffect describes an enduring shift in the perception of the spatial location of acoustic stimuli after a period of exposure of spatially disparate and simultaneously presented acoustic and visual stimuli. Exposure of a mismatch of 8 degrees for 20-30 min is sufficient to shift the perception of acoustic space by approximately the same amount across subjects and acoustic frequencies. Given that the cerebral cortex is necessary for the perception of acoustic space, it is likely that the ventriloquism aftereffect reflects a change in the cortical representation of acoustic space. Comparisons between the responses of single cortical neurons in the behaving macaque monkey and the stimulus parameters that give rise to the ventriloquism aftereffect suggest that the changes in the cortical representation of acoustic space may begin as early as the primary auditory cortex.