Search

OBJECTIVE The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model. METHODS An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6-0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis. RESULTS The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18-labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes. CONCLUSIONS The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.

Dyspnoea has distinct sensory modalities, including air hunger and the sensation of excessive breathing "work/effort". Both have analgesic properties. In the case of work/effort, spinal mechanisms have been documented (inhibitory effect on the spinal nociceptive flexor reflex, RIII). This mechanism involves C-fibres. As C-fibres are unlikely to play a major role in air hunger, we hypothesised that inducing this type of dyspnoea would not result in RIII inhibition. Eight healthy volunteers were exposed to a hypercapnic hyperoxic gas mixture (5% CO2 and 95% O2) and asked to voluntarily fight the corresponding ventilatory reflex response by reducing tidal volume below its spontaneous level. Ventilatory variables and dyspnoea intensity (ordinal scale) were measured. Electromyography of the biceps femoris was used to record the amplitude of RIII in response to painful electrical sural nerve stimulation. Air hunger failed to inhibit the RIII reflex. We conclude that the mechanisms of air hunger induced analgesia do not include a spinal contribution and are therefore mostly central., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Experimentally induced pain can be attenuated by concomitant heterotopic nociceptive stimuli (counterirritation). Animal data indicate that this stems from supraspinal "diffuse noxious inhibitory controls" (DNICs) triggered by C and Aδ fibers. In humans, only noxious stimuli induce counterirritation. This points at C fibers, but the effects of pharmacologically stimulating C fibers have not been studied. Intravenous adenosine activates pulmonary C fibers and induces dyspnea. This study tests the hypothesis that putative activation of pulmonary C fibers by adenosine would trigger DNICs in humans and induce counterirritation. Twelve healthy volunteers were included (with valid results available in 9) and studied according to a double-blind, randomized, cross-over design (intravenous adenosine, 140 μg·kg(-1)·min(-1), during 5 min vs. placebo). We measured ventilatory variables and end-tidal CO2 tension, dyspnea intensity by visual analog scale, and the intensity of putative chest pain. The primary outcome was the amplitude of the RIII component of the nociceptive flexor reflex recorded by biceps femoris electromyogram in response to painful electrical sural nerve stimulation (RIII), taken as a substitute for pain perception. Placebo did not induce any significant effect. Adenosine induced dyspnea, hyperpnea, tachycardia, and significant RIII inhibition (24 ± 8% at the 4th min, P < 0.0001). The temporal dynamics of adenosine-induced dyspnea and RIII inhibition differed (immediate onset followed by a slow decrease for dyspnea, slower onset for RIII inhibition). Intravenous adenosine in normal humans induces counterirritation, fueling the notion that C-fiber stimulation trigger DNICs in humans. The temporal dissociation between adenosine-induced dyspnea and RIII inhibition suggests that C fibers other than pulmonary ones might be involved.

Introduction: The prognosis for cases of idiopathic facial palsy is usually good. However, some cases develop disabling sequelae, such as synkinesis or severe facial hemispasm, despite targeted medical treatment., Objectives: The authors try to achieve that electromyography is useful to identify patients with severe palsy and an unfavourable prognosis. These patients would probably benefit from facial nerve decompression., Setting: The otolaryngology-head and neck surgery department of Pitié-Salpêtrière Hospital, Paris, a tertiary referral centre., Participants: Thirteen cases undergoing surgery between January 1997 and March 2007., Main Outcome Measures: We describe the electromyographic findings that led to surgery. All patients underwent surgery via a subpetrous approach, within four months of the onset of palsy. Decompression involved the first and second portions of the nerve and the geniculate ganglion., Results: Recovery to House-Brackmann grade III was obtained in all cases at one year follow up., Conclusion: These results compared favourably with previous reports. A new therapeutic procedure may allow improved results.

It is currently unknown whether the antidepressant effect of repetitive transcranial magnetic stimulation (rTMS) depends on specific characteristics of the stimulated frontal area, such as metabolic changes. We investigated the effect of high-frequency rTMS, administered over the most hypometabolic prefrontal area in depressed patients in a two-site, double-blind, randomized placebo-controlled add-on study. Forty-eight patients with medication-resistant major depression underwent magnetic resonance imaging and [(18)F]-fluorodeoxyglucose positron emission tomography (PET) in order to determine a target area for rTMS. After randomization to PET-guided (n = 16), standard (n = 18), or sham rTMS (n = 14) conditions, the patients received 10 sessions of 10-Hz rTMS (1600 pulses/session) at 90% motor threshold. Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) scores did not differ between PET-guided, standard and sham groups at 2-wk end-point. Exploratory comparison of left PET-guided (n = 9), right PET-guided, standard, and sham rTMS revealed significant effects. The highest improvement in MADRS scores was observed with left PET-guided (60 + or - 31%), significantly superior to sham (30 + or - 37%, p = 0.01) and right-guided (31 + or - 33%, p = 0.02) stimulation. Comparison between left PET-guided and standard rTMS (49 + or - 28%) was not significant (p = 0.12). Comparison between stimulation over dorsolateral prefrontal cortex (BA 9-46), stimulation of other areas, and sham rTMS was statistically significant. Stimulation over BA 9-46 region (n = 15) was superior to sham rTMS (p = 0.02). The results do not support the general hypothesis of increased antidepressant effects of high-frequency rTMS with prefrontal hypometabolism-related PET guidance. Nonetheless, whether metabolism and anatomy characteristics of left frontal area underneath the coil might account for an increase or speeding up of rTMS effects needs further investigation.

Objectives: To review the scientific literature regarding pain and schizophrenia, examine the empirical basis for the reported pain insensitivity of schizophrenia, and to emphasize the distinction between behavioral responses to pain or self-reported pain and physiologic response to painful stimuli., Methods: A Medline/Oldmedline search was conducted through 2006 using the key words schizophrenia and psychosis combined with pain and related terms designated by the International Association for the Study of Pain. Out of 431 articles initially identified, 57 were considered relevant and classified in 4 groups: case reports (n=9), clinical studies (n=23), experimental research (n=20), and review articles (n=5)., Results: Case reports and clinical studies reported reduced pain reactivity in patients with schizophrenia compared with healthy controls or other psychiatric patients. Similarly, experimental studies using self-report measures of pain reactivity generally reported higher pain perception thresholds in patients with schizophrenia. However, the only experimental study using a neurophysiologic measure of pain reactivity (the nociceptive RIII reflex) demonstrated a normal pain threshold in schizophrenia., Discussion: Review of clinical and experimental data indicates that in most situations behavioral pain reactivity and self-reported responses to pain are reduced in schizophrenia. However, there is little or no physiologic evidence supporting pain insensitivity in schizophrenia. It can be suggested that the widely accepted notion of reduced pain sensitivity in schizophrenia is related more to a different mode of pain expression than to a real endogenous analgesia. Further studies are required and potential directions for future research are proposed to clarify this issue.

Congenital insensitivity to pain (CIP) is a rare syndrome with various clinical expressions, characterized by a dramatic impairment of pain perception since birth. In the 1980s, progress in nerve histopathology allowed to demonstrate that CIP was almost always a manifestation of hereditary sensory and autonomic neuropathies (HSAN) involving the small-calibre (A-delta and C) nerve fibres which normally transmit nociceptive inputs along sensory nerves. Identification of the genetic basis of several clinical subtypes has led to a better understanding of the mechanisms involved, emphasizing in particular the crucial role of nerve growth factor (NGF) in the development and survival of nociceptors. Recently, mutations of the gene coding for the sodium channel Nav1.7--a voltage-dependent sodium channel expressed preferentially on peripheral nociceptors and sympathetic ganglia--have been found to be the cause of CIP in patients showing a normal nerve biopsy. This radical impairment of nociception mirrors the hereditary pain syndromes associated with "gain of function" mutations of the same ion channel, such as familial erythromelalgia and paroxysmal extreme pain disorder. Future research with CIP patients may identify other proteins specifically involved in nociception, which might represent potential targets for chronic pain treatment. Moreover, this rare clinical syndrome offers the opportunity to address interesting neuropsychological issues, such as the role of pain experience in the construction of body image and in the empathic representation of others' pain.

Purpose: To measure phrenic nerve conduction velocity in the neck in humans., Scope: We studied 15 healthy subjects (9 men, 32.4+/-6.7). We performed bipolar electrical phrenic stimulation in the neck, from a distal and a proximal stimulation site, and recorded diaphragm electromyographic responses on the surface of the chest. The ratio of the between-site distance to the latency difference provided phrenic velocities. Ulnar motor velocity was assessed similarly. In addition, five homogeneous patients with Charcot-Marie-Tooth disease type 1A (CMT1A) were studied for validation purposes. We obtained diaphragmatic responses from the two stimulation sites in all cases. The distal latencies (anterior axillary line recording) were 6.51+/-0.63ms (right) and 6.13+/-0.64ms (left). The minimal between site distance was 39mm. Phrenic motor velocity was 55.2+/-6.3ms(-1) (right) and 56.3+/-7.2ms(-1) (left). In CMT1A, phrenic velocities were 17.1+/-8.1ms(-1) (from 7 to 32ms(-1)) and were similar to ulnar and median velocities., Conclusions: Phrenic nerve velocities can be estimated in humans and compare with upper limb motor conduction velocities. This should refine the investigation of phrenic function in peripheral neuropathies.

Three characteristic observations are presented along with three tables presenting 24 patients with the following elements in common: excessively repeated use of an instrument such as a pen, a musical instrument or a tool. The appearance after that use of a central pathological phenomenon that includes a local dystonia of a hand or the mouth, a tremor, or the association of a tremor and a dystonia, all within the muscular domain corresponding to that of the use. The discussion, which is based exclusively on the clinical findings, deals with the following elements: the role of the use of the instrument rather than task itself, the predominant pathogenic factor which is the repetitive action, to which is added a genetic component in one incompletely penetrant case of DYT 1, and a probable genetic susceptibility in the others. The absence of improvement with rest distinguishes this central pathology from rheumatologic or orthopaedic problems involving repetitive activities. The evolution is slowly declining when the responsible action is continued. This occurs in three stages: a specific disorder involving only the use of the particular instrument, a more enlarged involvement affecting other activities and eventually a dystonia associated with a tremor or a postural tremor always located to the initial area. The therapeutic interventions suggested by the pathologic role of the repetitive movement is: (1) to advise a new training for the instrument that excludes the habitual movement; (2) to advise the patient to vary any newly acquired repetitive movements.

Unconscious mental representations elicited by subliminal stimuli are marked by their fleeting lifetimes, usually below 1 s. Can such evanescent subliminal stimuli, nevertheless, lead to long-lasting learning? To date, evidence suggesting a long-term influence of briefly perceived stimuli on behaviour or brain activity is scarce and questionable. In this study, we used intracranial recordings to provide the first direct demonstration that unconsciously perceived subliminal words could exert long-lasting effects on neuronal signals. When repeating subliminal words over long interstimulus intervals, we observed electrophysiological repetition effects. These unconscious repetition effects suggest that the single presentation of a masked word can durably affect neural architecture.

Dyspnea, a leading respiratory symptom, shares many clinical, physiological, and psychological features with pain. Both activate similar brain areas. The neural mechanisms of dyspnea are less well described than those of pain. The present research tested the hypothesis of common pathways between the two sensations. Six healthy men (age 30-40 yr) were studied. The spinal nociceptive flexion reflex (RIII) was first established in response to electrical sural stimulation. Dyspnea was then induced through inspiratory threshold loading, forcing the subjects to develop 70% of their maximal inspiratory pressure to inhale. This led to progressive inhibition of the RIII reflex that reached 50 +/- 12% during the fifth minute of loading (P < 0.001), was correlated to the intensity of the self-evaluated respiratory discomfort, and had recovered 5 min after removal of the load. The myotatic H-reflex was not inhibited by inspiratory loading, arguing against postsynaptic alpha motoneuron inhibition. Dyspnea, like pain, thus induced counterirritation, possibly indicating a C-fiber stimulation and activation of diffuse noxious inhibitory descending controls known to project onto spinal dorsal horn wide dynamic range neurons. This confirms the noxious nature of certain types of breathlessness, thus opening new physiological and perhaps therapeutic perspectives.

Study Objective: To identify the neural structures and pathways underlying cataplexy during status cataplecticus in a narcoleptic patient, using brain perfusion single photon emission computed tomography (SPECT)., Methods: A 68-year-old woman with hypocretin-deficient narcolepsy-cataplexy suffered status cataplecticus after having stopped clomipramine. She underwent a 99mTc-ethylcysteinate dimer brain SPECT during an episode of cataplexy; this image was compared with her brain SPECT during an intervening asymptomatic period. Subtraction SPECT coregistered to magnetic resonance imaging (MRI)(SISCOM)-determined anatomic areas differentially perfused during cataplexy and basal wakefulness state., Results: The areas hyperactivated during cataplexy corresponded on brain MRI with the cingular area, the left and right orbitofrontal cortex, the right temporal cortex, and the right putamen. No significant hypoperfused region was observed during the cataplectic episode., Discussion: Cataplexy during status cataplecticus partially resembles normal rapid eye movement sleep (with high cingular, orbitofrontal, and putamen activity) but without the other imaging characteristics of this state (no hyperactivation of the pons, amygdale, or occipital cortex).

Although normal subjects do not move during REM sleep, patients with Parkinson's disease may experience REM sleep behaviour disorder (RBD). The characteristics of the abnormal REM sleep movements in RBD have, however, not been studied. We interviewed one hundred consecutive non-demented patients with Parkinson's disease and their bed partners using a structured questionnaire assessing the presence of RBD. They rated the quality of movements, voice and facial expression during RBD as being better, equal or worse than in awake ON levodopa condition. Night-time sleep and movements were video-monitored during polysomnography in 51 patients to evaluate the presence of bradykinesia, tremor and hypophonia during REM sleep. Fifty-nine patients had clinical RBD with 53/59 bed partners able to evaluate them. All 53 (100%) reported an improvement of at least one component of motor control during RBD. By history, movements were improved in 87% patients (faster, 87%; stronger, 87%; smoother, 51%), speech was better in 77% patients (more intelligible, 77%; louder, 38%; better articulated, 57%) and facial expression was normalized in 47% patients. Thirty-eight per cent of bed partners reported that movements were 'much better', even in the most disabled patients. The video-monitored purposeful movements in REM sleep were also surprisingly fast, ample, coordinated and symmetrical, without obvious sign of parkinsonism. The movements were, however, jerky, violent and often repetitive. While all patients had asymmetrical parkinsonism when awake, most of the time they used the more disabled arm, hand and leg during the RBD (P = 0.04). Movements involved six times as often the upper limbs and the face as the lower limbs (OR: 5.9, P = 0.004). The percentage of time containing tremor EMG activity decreased with sleep stages from 34.9 +/- 15.5% during wakefulness, to 3.6 +/- 5.7% during non-REM sleep stages 1-2, 1.4 +/- 3.0% during non-REM sleep stages 3-4, and 0.06 +/- 0.2% during REM sleep (in this last case, it was subclinical tremor). The restored motor control during REM sleep suggests a transient 'levodopa-like' reestablishment of the basal ganglia loop. Alternatively, parkinsonism may disappear by REM sleep-related disjunction between pyramidal and extrapyramidal systems. We suggest the following model: the movements during the RBD would be generated by the motor cortex and would follow the pyramidal tract bypassing the extrapyramidal system. These movements would eventually be transmitted to lower motor neurons because of brainstem lesions interrupting the pontomedullary pathways which mediate the REM sleep atonia.

Empathy is a complex form of psychological inference that enables us to understand the personal experience of another person through cognitive/evaluative and affective processes. Recent findings suggest that empathy for pain may involve a 'mirror-matching' simulation of the affective and sensory features of others' pain. Despite such evidence for a shared representation of self and other pain at the neural level, the possible influence of the observer's own sensitivity to pain upon his perception of others' pain has not been investigated yet. The aim of this study was to explore how patients with congenital insensitivity to pain (CIP), who are largely deprived of common stimulus-induced pain experiences, perceive the pain of others. Ratings of verbally presented imaginary painful situations showed that CIP patients' semantic knowledge regarding the pain of others did not differ from control subjects. Moreover, the propensity to infer pain from facial expressions was very similar between CIP patients and control subjects. On the other hand, when asked to rate pain-inducing events seen in video clips in the absence of visible or audible pain-related behaviour, CIP patients showed more variable and significantly lower pain ratings, as well as a reduction in aversive emotional responses, compared with control subjects. Interestingly, pain judgements, inferred either from facial pain expressions or from pain-inducing events, were strongly related to inter-individual differences in emotional empathy among CIP patients, while such correlation between pain judgement and empathy was not found in control subjects. The results suggest that a normal personal experience of pain is not necessarily required for perceiving and feeling empathy for others' pain. In the absence of functional somatic resonance mechanisms shaped by previous pain experiences, others' pain might be greatly underestimated, however, especially when emotional cues are lacking, unless the observer is endowed with sufficient empathic abilities to fully acknowledge the suffering experience of others in spite of his own insensitivity.

Cold hyperalgesia is a major clinical phenomenon, but validated experimental models are still lacking for humans. Topical menthol application has recently been proposed as a possible model for the study of cold pain. We characterized the psychophysical effects of 30% l-menthol in ethanol on glabrous skin in 39 healthy subjects, using a double-blind, randomized, crossover design, with ethanol as a control. Psychophysical testing included an assessment of pain thresholds and detection of mechanical, cold, and heat stimuli, and of the sensations induced by suprathreshold stimuli. Most subjects (90%) perceived a cooling sensation with menthol. Menthol decreased cold pain thresholds and enhanced pain responses to suprathreshold noxious cold stimuli, without affecting responses to other stimuli. Menthol therefore has selective effects on noxious cold processing. No subject displayed signs of skin irritation or redness. These data suggest that 30% menthol application may be a useful experimental model for studies of cold hyperalgesia in humans. The absence of local skin reactions also makes this test potentially suitable for use in patients.

The aim of this work was to determine the role of peripheral facial muscle reinnervation in the central reorganization of the blink reflex (BR) after hypoglossal-facial anastomosis (HFA). An electrophysiological study was performed on seven patients who underwent HFA after facial nerve transection during surgery for acoustic neuroma. HFA was performed within 15 days after surgery in five patients (group 1) and later for the two others (group 2). We studied the motor responses (MR) and the BR evoked on the affected side, before and over 3 years after the HFA. The MR appeared by the third month for the first group, and by the sixth and twelfth for the second group. After 36 months, the amplitude of MR was significantly higher than its control value, showing hyperinnervation of the facial muscles. Study of the BR evoked only an R1-type blink response that was observed 4 and 6 months after the MR for groups 1 and 2, respectively. This central reorganization appeared closely correlated with muscle reinnervation and its related timing. The occurrence of peripheral nerve-muscle contacts seems to be a necessary condition for reorganization of the trigemino-hypoglossal-facial reflex., (Muscle Nerve, 2006.)

The flexion or flexor reflex (FR) recorded in the lower limbs in humans (LLFR) is a widely investigated neurophysiological tool. It is a polysynaptic and multisegmental spinal response that produces a withdrawal of the stimulated limb and resembles (having several features in common) the hind-paw FR in animals. The FR, in both animals and humans, is mediated by a complex circuitry modulated at spinal and supraspinal level. At rest, the LLFR (usually obtained by stimulating the sural/tibial nerve and by recording from the biceps femoris/tibial anterior muscle) appears as a double burst composed of an early, inconstantly present component, called the RII reflex, and a late, larger and stable component, called the RIII reflex. Numerous studies have shown that the afferents mediating the RII reflex are conveyed by large-diameter, low-threshold, non-nociceptive A-beta fibers, and those mediating the RIII reflex by small-diameter, high-threshold nociceptive A-delta fibers. However, several afferents, including nociceptive and non-nociceptive fibers from skin and muscles, have been found to contribute to LLFR activation. Since the threshold of the RIII reflex has been shown to correspond to the pain threshold and the size of the reflex to be related to the level of pain perception, it has been suggested that the RIII reflex might constitute a useful tool to investigate pain processing at spinal and supraspinal level, pharmacological modulation and pathological pain conditions. As stated in EFNS guidelines, the RIII reflex is the most widely used of all the nociceptive reflexes, and appears to be the most reliable in the assessment of treatment efficacy. However, the RIII reflex use in the clinical evaluation of neuropathic pain is still limited. In addition to its nocifensive function, the LLFR seems to be linked to posture and locomotion. This may be explained by the fact that its neuronal circuitry, made up of a complex pool of interneurons, is interposed in motor control and, during movements, receives both peripheral afferents (flexion reflex afferents, FRAs) and descending commands, forming a multisensorial feedback mechanism and projecting the output to motoneurons. LLFR excitability, mediated by this complex circuitry, is finely modulated in a state- and phase-dependent manner, rather as we observe in the FR in animal models. Several studies have demonstrated that LLFR excitability may be influenced by numerous physiological conditions (menstrual cycle, stress, attention, sleep and so on) and pathological states (spinal lesions, spasticity, Wallenberg's syndrome, fibromyalgia, headaches and so on). Finally, the LLFR is modulated by several drugs and neurotransmitters. In summary, study of the LLFR in humans has proved to be an interesting functional window onto the spinal and supraspinal mechanisms of pain processing and onto the spinal neural control mechanisms operating during posture and locomotion.

Nociceptive signals are generated by peripheral sensory organs called nociceptors, which are endings of small-diameter nerve fibers responsive to the tissue environment. The myriad chemical mediators capable of activating, sensitizing, or arousing nociceptors include kinins, proinflammatory and anti-inflammatory cytokines, prostanoids, lipooxygenases, the "central immune response mediator" NF-kappaB, neurotrophins and other growth factors, neuropeptides, nitric oxide, histamine, serotonin, proteases, excitatory amino acids, adrenergic amines, and opioids. These mediators may act in combination or at a given time in the inflammatory process, producing subtle changes that result in hyperalgesia or allodynia. We will review the most extensively studied molecular and cellular mechanisms underlying these two clinical abnormalities. The role of the peripheral nervous system in progression of inflammatory joint disease to chronicity is discussed.

Missense mutations in the human skeletal muscle Na+ channel alpha subunit (hSkM1) are responsible for a number of muscle excitability disorders. Among them, paramyotonia congenita (PC) is characterized by episodes of muscle stiffness induced by cold and aggravated by exercise. We have identified a new PC-associated mutation, which substitutes aspartic acid for a conserved alanine in the S4-S5 linker of domain III (A1152D). This residue is of particular interest since its homologue in the rat brain type II Na+ channel has been suggested as an essential receptor site for the fast inactivation particle. To identify the biophysical changes induced by the A1152D mutation, we stably expressed hSkM1 mutant or wild-type (WT) channels in HEK293 (human embryonic kidney) cells, and recorded whole-cell Na+ currents with the patch-clamp technique. Experiments were performed both at 21 and 11 degrees C to better understand the sensitivity to cold of paramyotonia. The A1152D mutation disrupted channel fast inactivation. In comparison to the WT, mutant channels inactivated with slower kinetics and displayed a 5 mV depolarizing shift in the voltage dependence of the steady-state. The other noticeable defect of A1152D mutant channels was an accelerated rate of deactivation from the inactivated state. Decreasing temperature by 10 degrees C amplified the differences in channel gating kinetics between mutant and WT, and unveiled differences in both the sustained current and channel deactivation from the open state. Overall, cold-exacerbated mutant defects may result in a sufficient excess of Na+ influx to produce repetitive firing and myotonia. In the light of previous reports, our data point to functional as well as phenotypic differences between mutations of conserved S4-S5 residues in domains II and III of the human skeletal muscle Na+ channel.

Recruitment of executive attention is normally associated to a subjective feeling of mental effort. Here we investigate the nature of this coupling in a patient with a left mesio-frontal cortex lesion including the anterior cingulate cortex (ACC), and in a group of comparison subjects using a Stroop paradigm. We show that in normal subjects, subjective increases in effort associated with executive control correlate with higher skin-conductance responses (SCRs). However, our patient experienced no conscious feeling of mental effort and showed no SCR, in spite of exhibiting normal executive control, and residual right anterior cingulate activity measured with event-related potentials (ERPs). Finally, this patient demonstrated a pattern of impaired behavior and SCRs in the Iowa gambling task-elaborated by Damasio, Bechara and colleagues-replicating the findings reported by these authors for other patients with mesio-frontal lesions. Taken together, these results call for a theoretical refinement by revealing a decoupling between conscious cognitive control and consciously reportable feelings. Moreover, they reveal a fundamental distinction, observed here within the same patient, between the cognitive operations which are depending on normal somatic marker processing, and those which are withstanding to impairments of this system.

Myotonic syndromes and periodic paralyses are rare disorders of skeletal muscle characterized mainly by muscle stiffness or episodic attacks of weakness. Familial forms are caused by mutations in genes coding for skeletal muscle voltage-gated ion channels. Exercise is known to trigger, aggravate, or relieve the symptoms. Therefore, exercise can be used as a functional test in electromyography to improve the diagnosis of these muscle disorders. Abnormal changes in the compound muscle action potential can be disclosed using different exercise tests. We report the outcome of an inclusive electromyographic survey of a large population of patients with identified ion channel gene defects. Standardized protocols comprising short and long exercise tests were applied on 41 unaffected control subjects and on 51 case patients with chloride, sodium, or calcium channel mutations known to cause myotonia or periodic paralysis. These tests disclosed significant changes of compound muscle action potential, which generally matched the clinical symptoms. Combining the responses to the different tests defined five electromyographic patterns (I-V) that correlated with subgroups of mutations and may be used in clinical practice as guides for molecular diagnosis. We hypothesize that mutations are segregated into the different electromyographic patterns according to the underlying pathophysiological mechanisms.

Introduction: Neuromyotonia is a late and rare complication of radiation therapy, consisting of involuntary sustained muscle contractions with a delay in relaxation., Observation: We report the case of a 68-year-old man who developed neuromyotonia of the masseter muscle 6 years after irradiation for tonsil carcinoma., Conclusion: This observation underlines the importance of a correct diagnosis that can lead to an efficient treatment by carbamazepine.

Painful electrical stimulation of the fingers evokes an inhibitory response in hand muscles (cutaneous silent period, CSP). The aim of this study was to determine whether purely nociceptive thermal stimuli applied to the hand evoke a CSP. High-intensity laser pulses (205 +/- 44 mJ) were delivered to the dorsum and palm of the hand in five volunteers. Electromyographic signals were recorded from the ipsilateral first dorsal interosseous muscle. We then compared the laser-evoked CSP with the CSP induced by electrical stimulation. A clear laser CSP (latency 90 +/- 7 ms) was evoked in all subjects when laser pulses were applied to the palm of the hand, whereas no response was recorded after stimulation of the dorsum. Electrical stimulation of both the dorsum and the palm evoked a CSP (latency 65 +/- 5 ms), although the reflex threshold was significantly lower after stimulation of the palm. This study confirms that the CSP is a nociceptive response specific to limbs that grasp. In humans, palm nociceptors are probably more functionally effective than dorsal nociceptors in inducing the hand-muscle inhibition that interrupts hand prehension (so that a potentially noxious source is dropped) before proximal muscles withdraw the limb.

kinetic mustism is a dramatic deficit in spontaneous initiation of voluntary motor and speech acts, usually secondary to bilateral lesions of the anterior cingulate cortices and supplementary motor areas [Principles of Neurology, McGraw-Hill, New York, 1989]. Given the obvious limitations of traditional neuropsychological testing in this clinical context, the use of neurophysiological tools such as bedside auditory cognitive event-related potentials (ERPs), recently proven to be relevant to evaluate comatose and vegetative patients [Clin. Neurophysiol. 110 (9) (1999) 1601; News Physiol. Sci. 17 (2002) 38], may constitute an interesting alternative. Here, we present the ERPs of a 38-year-old right-handed woman with severe akinetic mutism recorded in a passive auditory odd-ball paradigm. In spite of this severe clinical state, we could observe the presence of a "Mismatch Negativity", and of a larger P300 in rare trials than in frequent ones. By revealing a high level of cognitive integration of environmental auditory information, our study emphasizes the potential clinical relevance of MMN and P300 recordings in akinetic mutism to assess patient cognitive functioning.

Paramyotonia congenita (PC) is a dominantly inherited skeletal muscle disorder caused by missense mutations in the SCN4A gene encoding the pore-forming alpha subunit (hSkM1) of the skeletal muscle Na+ channel. Muscle stiffness is the predominant clinical symptom. It is usually induced by exposure to cold and is aggravated by exercise. The most prevalent PC mutations occur at T1313 on DIII-DIV linker, and at R1448 on DIV-S4 of the alpha subunit. Only one substitution has been described at T1313 (T1313M), whereas four distinct amino-acid substitutions were found at R1448 (R1448C/H/P/S). We report herein a novel mutation at position 1313 (T1313A) associated with a typical phenotype of PC. We stably expressed T1313A or wild-type (hSkM1) channels in HEK293 cells, and performed a detailed study on mutant channel gating defects using the whole-cell configuration of the patch-clamp technique. T1313A mutation impaired Na+ channel fast inactivation: it slowed and reduced the voltage sensitivity of the kinetics, accelerated the recovery, and decreased the voltage-dependence of the steady state. Slow inactivation was slightly enhanced by the T1313A mutation: the voltage dependence was shifted toward hyperpolarization and its steepness was reduced compared to wild-type. Deactivation from the open state assessed by the tail current decay was only slowed at positive potentials. This may be an indirect consequence of disrupted fast inactivation. Deactivation from the inactivation state was hastened. The T1313A mutation did not modify the temperature sensitivity of the Na+ channel per se. However, gating kinetics of the mutant channels were further slowed with cooling, and reached levels that may represent the threshold for myotonia. In conclusion, our results confirm the role of T1313 residue in Na+ channel fast inactivation, and unveil subtle changes in other gating processes that may influence the clinical phenotype.

Hypoglossal-facial anastomosis (HFA) is a cross-over between the proximal stump of the hypoglossal nerve (XII) and the distal one of the facial nerve (VII). The hypoglossal axons regrow within the sheaths of facial fibres, allowing the progressive reinnervation of the facial muscles. This model is interesting to study some mechanisms of plasticity of the nervous system for several reasons: 1) It is a quite simple and reproducible model of pathophysiological state. It allows the study of 2) the modifications of the nervous system induced by the HFA, both upwards and downwards to the lesion and 3) the modifications of reflex activities involving intrapontine connections such as the blink reflex. The electrophysiological features of the trigemino-facial (TF) and trigemino-hypoglossal (TG) connections demonstrated that a central reorganisation of the blink reflex (BR) was induced by HFA: the afferent volleys of the TF and TH reflexes elicited by cutaneous and mucosal trigeminal afferents respectively have been shown to project onto common interneurones located within the trigeminal principal sensory nucleus. A long-term prospective study showed: 1) a reinnervation of the facial muscles by the hypoglossal axons is a necessary perequisite for the central reorganisation of BR, 2) a hyperinnervation of the facial muscles by the hypoglossal axons, 3) a transient and regressive cross-innervation of paralyzed face by the healthy contralateral facial nerve.

The authors investigated the evolution of the dynamic features of the cross-innervation process in patients with complete facial palsy due to facial nerve transection during surgery for acoustic neuroma removal followed by a hypoglossal-facial nerve anastomosis (HFA). Clinical and electrophysiologic investigations were carried out before and over a 3-year period after HFA. Cross-innervation had started by the 10th day, progressed to the seventh to eighth month, then decreased and finally disappeared by the 12th month after HFA. Ipsilateral reinnervation was observed by the fourth month, progressed to the 12th to 18th month, and remained stable for the remainder of the follow-up period.

Patients with peripheral nerve or spinal cord lesions frequently report perceptual distortions related to position, shape, texture or temperature of the affected areas. This study aimed to describe the phenomenology of such body image alterations during the course of upper limb, lower limb or spinal anaesthetic blocks in patients (n = 36) undergoing orthopaedic surgery. Multimodal sensory testing and assessment of motor function were performed at regular intervals, and the relationship between the reported body image distortions and the progression of sensory and motor impairment was analysed. We found that perceptual changes concerning the shape and size of the deafferented limb occurred in the great majority of patients. In all of them, illusions of swelling, elongation or shortening of the limb coincided with the impairment of warm, cold and/or pinprick sensations, suggesting that thin myelinated Adelta- and/or unmyelinated C-fibres may provide a source of tonic modulation to the limb's cortical representation. Such perceptual alterations of shape and size of body parts differed clearly from postural illusions in terms of frequency, time course and influence of vision. In addition to perceptual changes in the deafferented area, almost half of the patients felt their unanaesthetized lips and/or mouth swelling during the course of upper limb block, suggesting the unmasking of dynamic interactions between somatotopically adjacent cortical representations. Conflicting sensations could co-exist in the patient's body image, such as the illusion of swelling of a limb, which, at the same time, was felt to be missing. The sense of ownership of the deafferented limb was impaired in some cases. These observations show that the perception of body shape and the awareness of its postural variations are built from different plastic models. They also underline the contribution of peripheral afferent activity to the maintenance of a unified body image.

Objective: An open therapeutic trial was conducted in patients with Bell's palsy. Results were compared with data in the literature., Materials and Methods: Between 1997 and 2000, 76 patients with Bell's palsy were treated with intravenous methylprednisolone (2 mg/kg/day) and acyclovir (5-10 mg/kg/8 hours) for 7 days. Treatment was initiated in all patients before the 14th day of illness. Severity of the palsy was scored on the first day of treatment and again one year later using the House and Brackman scale., Results: Grade II or III palsy were observed in 38% of the patients at initial presentation, grades IV to VI in 62%. After treatment, 92% of the patients had reverted to grades I and II (good outcome) and only 8% had sequelae at 1-year follow-up. All patients with initial grade I or II recovered completely. For patients with grade IV, V, or VI complete recovery at 1 year was observed in 94, 86 and 50% respectively., Conclusion: Data in the literature suggest that corticosteroids should improve recovery in Bell's plasy. In our study, adjunction of acyclovir did not demonstrate any clear improvement in the cure rate. Benefit could depend on early prescription.

The effect of N-[(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithiol]-1-oxopropyl]-L-phenylalanine benzyl ester (RB101), a dual inhibitor of the enkephalin-degrading enzymes, neutral endopeptidase and aminopeptidase N, was assessed in anaesthetised rats on the C-fibre reflex elicited by electrical stimulation within the sural nerve territory and recorded from the ipsilateral biceps femoris muscle. The temporal evolution of the pharmacological response was monitored by the repeated application of a constant stimulus intensity, namely three times threshold (3 T). In addition, recruitment curves were built by varying the stimulus intensity from 0 to 7 T. RB101 (7.5, 15 and 30 mg kg(-1), i.v.) induced a dose-dependent, naloxone-reversible depression of the reflex, which lasted around 60 min with the highest dose. The ED(50) was calculated as 16.9 mg kg(-1). Analyses of the recruitment curves revealed: (1) a significant increase of threshold; (2) a significant depression of the reflex in the ascending part of the curve; and (3) a lack of major depressive effects on the responses elicited by the strongest stimuli (corresponding to the plateau of the curve). The increase in the nociceptive threshold by enkephalin-degrading enzyme inhibitors, confirms previous data obtained from behavioural tests. In addition, the present study revealed an efficacy of these compounds over a wide range of stimulus intensities, albeit excluding the highest.

The autosomal dominant mutation causing myotonic dystrophy (DM1) is a CTG repeat expansion in the 3'-UTR of the DM protein kinase (DMPK) gene. This multisystemic disorder includes myotonia, progressive weakness and wasting of skeletal muscle and extramuscular symptoms such as cataracts, testicular atrophy, endocrine and cognitive dysfunction. The mechanisms underlying its pathogenesis are complex. Recent reports have revealed that DMPK gene haploinsufficiency may account for cardiac conduction defects whereas cataracts may be due to haploinsufficiency of the neighboring gene, the DM-associated homeobox protein (DMAHP or SIX5) gene. Furthermore, mice expressing the CUG expansion in an unrelated mRNA develop myotonia and myopathy, consistent with an RNA gain of function. We demonstrated that transgenic mice carrying the CTG expansion in its human DM1 context (>45 kb) and producing abnormal DMPK mRNA with at least 300 CUG repeats, displayed clinical, histological, molecular and electrophysiological abnormalities in skeletal muscle consistent with those observed in DM1 patients. Like DM1 patients, these transgenic mice show abnormal tau expression in the brain. These results provide further evidence for the RNA trans-dominant effect of the CUG expansion, not only in muscle, but also in brain.