The cerebral metabolic ratio is not affected by oxygen availability during maximal exercise in humans.

Intense exercise decreases the cerebral metabolic ratio of O(2) to carbohydrates (glucose + (1/2) lactate) and the cerebral lactate uptake depends on its arterial concentration, but whether these variables are influenced by O(2) availability is not known. In six males, maximal ergometer rowing increased the arterial lactate to 21.4 +/- 0.8 mm (mean +/- s.e.m.) and arterial-jugular venous (a-v) difference from -0.03 +/- 0.01 mm at rest to 2.52 +/- 0.03 mm (P < 0.05). Arterial glucose was raised to 8.5 +/- 0.5 mm and its a-v difference increased from 1.03 +/- 0.01 to 1.86 +/- 0.02 mm (P < 0.05) in the immediate recovery. During exercise, the cerebral metabolic ratio decreased from 5.67 +/- 0.52 at rest to 1.70 +/- 0.23 (P < 0.05) and remained low in the early recovery. Arterial haemoglobin O(2) saturation was 92.5 +/- 0.2% during exercise with room air, and it reached 87.6 +/- 1.0% and 98.9 +/- 0.2% during exercise with an inspired O(2) fraction of 0.17 and 0.30, respectively. Whilst the increase in a-v lactate difference was attenuated by manipulation of cerebral O(2) availability, the cerebral metabolic ratio was not affected significantly. During maximal rowing, the cerebral metabolic ratio reaches the lowest value with no effect by a moderate change in the arterial O(2) content. These findings suggest that intense whole body exercise is associated with marked imbalance in the cerebral metabolic substrate preferences independent of oxygen availability.

Reduced reciprocal inhibition is seen only in spastic limbs in patients with neurolathyrism.

If reduced reciprocal inhibition plays a causal role in the pathophysiology of spasticity as has been suggested in several studies, the inhibition is expected to be impaired in spastic, but not in normal muscles. Patients with neurolathyrism offer a possibility of testing this prediction since the spastic symptoms in these patients are restricted to the lower extremities only. Three patients with neurolathyrism were tested. Their data were compared with 15 age-matched healthy subjects. All patients showed signs of spasticity in the legs. Two patients had normal voluntary muscle force in the lower extremities and one had decreased force. No clinical abnormalities were found in the upper extremities. Reciprocal inhibition between ankle dorsiflexor and plantarflexor muscles was absent in all patients, whereas the inhibition between wrist extensor and flexor muscles was present and of normal size and latency. These findings are consistent with the hypothesis that reduced reciprocal inhibition plays a causal role in the pathophysiology of spasticity.

Reciprocal inhibition and corticospinal transmission in the arm and leg in patients with autosomal dominant pure spastic paraparesis (ADPSP).

The pathophysiological mechanisms underlying the development of spasticity are not clear, but the excitability of the disynaptic reciprocal inhibitory pathway is affected in many patients with spasticity of different origin. Patients with genetically identified autosomal dominant pure spastic paraparesis (ADPSP) develop spasticity and paresis in the legs, but usually have no symptoms in the arms. Comparison of the spinal and supraspinal control of the legs and arms in these patients may therefore provide valuable information about the pathophysiology of spasticity. In the present study, we tested the hypothesis that one of the pathophysiological mechanisms of spasticity in these patients is abnormal corticospinal transmission and that this may lead to decreased reciprocal inhibition. Ten patients and 15 healthy age-matched control subjects were investigated. The patients were all spastic in the legs (with hyperactive tendon reflexes, increased muscle tone and Babinski sign), but had no neurological symptoms in the arms (except for one patient). Disynaptic reciprocal Ia inhibition of flexor carpi radialis (FCR) and soleus (SOL) motoneurons was measured (as the depression of the background FCR and SOL EMG activity and as the short latency inhibition of the FCR and SOL H-reflex evoked by radial and peroneal nerve stimulation). In addition, the latency of motor evoked potentials (MEPs) in the FCR muscle and the tibialis anterior (TA) muscle was measured. In the patients, the mean reciprocal inhibition was normal in the arms, while it was significantly decreased in the leg compared with the healthy subjects. In the patients, the average latency of MEPs in the FCR muscle was normal, while the latency to the MEP in TA muscle was significantly longer than that found in healthy subjects. Four patients, however, differed from the other patients by having significant reciprocal inhibition in the leg and a significantly shorter latency of TA MEPs than found in the other patients. The six patients without reciprocal inhibition in the leg instead had significant short latency facilitation of the SOL H-reflex and a longer TA MEP latency than seen in the healthy subjects and in the four patients with retained reciprocal inhibition. These findings support the hypothesis that disynaptic reciprocal inhibition and short latency facilitation are involved in the development of spasticity and, furthermore, they suggest a positive correlation between impairment of corticospinal transmission and decrease of reciprocal inhibition/appearance of reciprocal facilitation.

Corticospinal transmission to leg motoneurones in human subjects with deficient glycinergic inhibition.

Normal coordinated movement requires that the activity of antagonistic motoneurones may be depressed at appropriate times during the movement. Both glycinergic and GABAergic inhibitory mechanisms participate in this control. Patients with the major form of hyperekplexia (hereditary startle disease) have impaired inhibition of spinal motoneurones from local glycinergic interneurones and represent an ideal opportunity for studying the role of glycinergic inhibition in the control of antagonistic muscles. In the present study we investigated whether impaired glycinergic inhibition affects the corticospinal control of antagonistic spinal motoneurones in 10 patients with hyperekplexia and whether there are mechanisms that may compensate for the lack of glycinergic inhibition. In healthy subjects transcranial magnetic stimulation (TMS) produced a short-latency inhibition of the soleus H-reflex at rest and during tonic dorsiflexion. This inhibition, which has been shown to be mediated by spinal (glycinergic) inhibitory interneurones, was absent in all four patients in whom this experiment was performed. This confirms that glycinergic transmission is impaired in the patients. During voluntary dorsiflexion subthreshold TMS produced a depression of the ongoing EMG activity in the tibialis anterior (TA) muscle in both healthy subjects and all of the six tested patients. This is consistent with the idea that this EMG depression is caused by activation of cortical (GABAergic) inhibitory interneurones. Cross-correlation analysis revealed normal short-term synchronization of TA motor units accompanied by coherence in the 8-12 Hz and 18-35 Hz frequency bands in the 10 patients. As in healthy subjects, 8-12 Hz coherence accompanied by decreased tendency to discharge synchronously (de-synchronization) was found in recordings from the antagonistic TA and soleus muscles in 2 of the 10 patients. This suggests that glycinergic inhibition is not responsible for de-synchronization of antagonistic motor units, but that other GABAergic-inhibitory mechanisms must be involved. We propose that such mechanisms may compensate for the lack of glycinergic reciprocal inhibition in the hyperekplectic patients and explain why voluntary movements are not more severely affected.

Coupling of antagonistic ankle muscles during co-contraction in humans.

In 35 healthy human subjects coupling of EMGs recorded from the tibialis anterior (TA) and soleus (Sol) muscles during voluntary co-contraction was analysed in the time and frequency domains. Two patterns were observed in different subjects or in the same subject on different occasions. One pattern consisted of central peaks in the cumulant density function of the two signals, which was often accompanied by coherence in the 15-35 Hz frequency band. The other pattern consisted of a central trough in the cumulant density function, which was mostly accompanied by coherence around 10 Hz. When this was the case oscillations were usually observed in the cumulant density function with time lags of 100 ms. Both patterns could be observed in the same subject, but usually not at the same time. Coherence around 10 Hz associated with a central trough in the cumulant density function was less common during weak than during strong co-contraction. The central peak with coherence in the 15-35 Hz frequency band in contrast tended to be most common during weak contraction. There was a tendency for the 10-Hz coherence with central trough to occur when the contractions had been maintained for some time. Both patterns could be observed when sensory feedback in large diameter afferents was blocked by ischaemia. When a central peak with coherence in the 15-35 Hz frequency band was observed for paired TA and Sol EMG recordings (10 out of 19 subjects), a coupling in the same frequency band was also observed between the EMG activities from the two muscles and the EEG activity recorded from the leg area of the motor cortex. When the central trough and the coherence around 10 Hz was observed for the EMG recordings (8 out of 19 subjects), no significant coherence was observed between EEG and EMG in 7 of the 8 subjects. In the last subject coherence around 10 Hz was observed. It is suggested that these findings signify the existence of two different central input systems to antagonistic ankle motoneurones: one input activates one muscle while depressing the antagonist and the other coactivates antagonistic motoneurones. The data suggest that at least the latter input depends on motor cortical activity.

Interaction of transcranial magnetic stimulation and electrical transmastoid stimulation in human subjects.

Transcranial magnetic stimulation activates corticospinal neurones directly and transsynaptically and hence, activates motoneurones and results in a response in the muscle. Transmastoid stimulation results in a similar muscle response through activation of axons in the spinal cord. This study was designed to determine whether the two stimuli activate the same descending axons. Responses to transcranial magnetic stimuli paired with electrical transmastoid stimuli were examined in biceps brachii in human subjects. Twelve interstimulus intervals (ISIs) from -6 ms (magnet before transmastoid) to 5 ms were investigated. When responses to the individual stimuli were set at 10-15 % of the maximal M-wave, responses to the paired stimuli were larger than expected at ISIs of -6 and -5 ms but were reduced in size at ISIs of -2 to 1 ms and at 3 to 5 ms. With individual responses of 3-5 % of maximal M-wave, facilitation still occurred at ISIs of -6 and -5 ms and depression of the paired response at ISIs of 0, 1, 4 and 5 ms. The interaction of the response to transmastoid stimulation with the multiple descending volleys elicited by magnetic stimulation of the cortex is complex. However, depression of the response to the paired stimuli at short ISIs is consistent with an occlusive interaction in which an antidromic volley evoked by the transmastoid stimulus collides with and annihilates descending action potentials evoked by the transcranial magnetic stimulus. Thus, it is consistent with the two stimuli activating some of the same corticospinal axons.

Suppression of EMG activity by transcranial magnetic stimulation in human subjects during walking.

1. The involvement of the motor cortex during human walking was evaluated using transcranial magnetic stimulation (TMS) of the motor cortex at a variety of intensities. Recordings of EMG activity in tibialis anterior (TA) and soleus muscles during walking were rectified and averaged. 2. TMS of low intensity (below threshold for a motor-evoked potential, MEP) produced a suppression of ongoing EMG activity during walking. The average latency for this suppression was 40.0 +/- 1.0 ms. At slightly higher intensities of stimulation there was a facilitation of the EMG activity with an average latency of 29.5 +/- 1.0 ms. As the intensity of the stimulation was increased the facilitation increased in size and eventually a MEP was clear in individual sweeps. 3. In three subjects TMS was replaced by electrical stimulation over the motor cortex. Just below MEP threshold there was a clear facilitation at short latency (approximately 28 ms). As the intensity of the electrical stimulation was reduced the size of the facilitation decreased until it eventually disappeared. We did not observe a suppression of the EMG activity similar to that produced by TMS in any of the subjects. 4. The present study demonstrates that motoneuronal activity during walking can be suppressed by activation of intracortical inhibitory circuits. This illustrates for the first time that activity in the motor cortex is directly involved in the control of the muscles during human walking.

Unexpected reflex response to transmastoid stimulation in human subjects during near-maximal effort.

1. In human subjects, a high-voltage electrical pulse between electrodes fixed over the mastoid processes activates descending tract axons at the level of the cervico-medullary junction to produce motor responses (cevicomedullary evoked responses; CMEPs) in the biceps brachii and brachioradialis muscles. 2. During isometric maximal voluntary contractions (MVCs) of the elbow flexors, CMEPs in the biceps brachii and brachioradialis muscles are sometimes followed by a second compound muscle action potential. This response can be observed in single trials (amplitude of up to 60 % of the maximal M wave) and follows the CMEP by about 16 ms in both muscles. The response only occurs during very strong voluntary contractions. 3. The second response following transmastoid stimulation appears with stimulation intensities that are at the threshold for evoking a CMEP in the contracting muscles. The response grows with increasing stimulus intensity, but then decreases in amplitude and finally disappears at high stimulation intensities. 4. A single stimulus to the brachial plexus during MVCs can also elicit a second response (following the M wave) in the biceps brachii and brachioradialis muscles. The latency of this response is 3-4 ms longer than that of the second response observed following transmastoid stimulation. This difference in latency is consistent with a reflex response to stimulation of large-diameter afferents. 5. The amplitude of the second response to transmastoid stimulation can be reduced by appropriately timed subthreshold transcranial magnetic stimuli. This result is consistent with intracortical inhibition of the response. 6. We suggest that transmastoid stimulation can elicit a large transcortical reflex response in the biceps brachii and brachioradialis muscles. The response travels via the motor cortex but is only apparent during near-maximal voluntary efforts.

Synchronization of lower limb motor unit activity during walking in human subjects.

Synchronization of motor unit activity was investigated during treadmill walking (speed: 3-4 km/h) in 25 healthy human subjects. Recordings were made by pairs of wire electrodes inserted into the tibialis anterior (TA) muscle and by pairs of surface electrodes placed over this muscle and a number of other lower limb muscles (soleus, gastrocnemius lateralis, gastrocnemius medialis, biceps femoris, vastus lateralis, and vastus medialis). Short-lasting synchronization (average duration: 9.6 +/- 1.1 ms) was observed between spike trains generated from multiunit electromyographic (EMG) signals recorded by the wire electrodes in TA in eight of nine subjects. Synchronization with a slightly longer duration (12.8 +/- 1.2 ms) was also found in 13 of 14 subjects for paired TA surface EMG recordings. The duration and size of this synchronization was within the same range as that observed during tonic dorsiflexion in sitting subjects. There was no relationship between the amount of synchronization and the speed of walking. Synchronization was also observed for pairs of surface EMG recordings from different ankle plantarflexors (soleus, medial gastrocnemius, and lateral gastrocnemius) and knee extensors (vastus lateralis and medialis of quadriceps), but not or rarely for paired recordings from ankle and knee muscles. The data demonstrate that human motor units within a muscle as well as synergistic muscles acting on the same joint receive a common synaptic drive during human gait. It is speculated that the common drive responsible for the motor unit synchronization during gait may be similar to that responsible for short-term synchronization during tonic voluntary contraction.

Modulation of presynaptic inhibition and disynaptic reciprocal Ia inhibition during voluntary movement in spasticity.

The aim of the study was to investigate whether impaired control of transmission in spinal inhibitory pathways contributes to the functional disability of patients with spasticity. To this end, transmission in the pathways mediating disynaptic reciprocal Ia inhibition and presynaptic inhibition was investigated in 23 healthy subjects and 20 patients with spastic multiple sclerosis during ankle dorsiflexion and plantar flexion. In healthy subjects, but not in spastic patients, the soleus H reflex was depressed at the onset of dorsiflexion (300 ms rise time, 20% of maximal voluntary effort). At the onset of plantar flexion, the soleus H reflex was more facilitated in the healthy subjects than in the patients. The H reflex increased more with increasing level of tonic plantar flexion and decreased more with dorsiflexion in the healthy subjects than in the spastic patients. Transmission in the disynaptic Ia reciprocal inhibitory pathway from ankle dorsiflexors to plantar flexors was investigated by conditioning the soleus H reflex by previous stimulation of the common peroneal nerve (conditioning-test interval 2-3 ms; stimulation intensity 1.05 times the motor response threshold). At the onset of dorsiflexion, stimulation of the common peroneal nerve evoked a significantly larger inhibition than at rest in the healthy subjects but not in the spastic patients. At the onset of plantar flexion the inhibition decreased in the healthy subjects, but because only weak inhibition was observed at rest in the patients it was not possible to determine whether a similar decrease occurred in this group. There were no differences in the modulation of inhibition during tonic plantar flexion and dorsiflexion in the two populations. Presynaptic inhibition of Ia afferents terminating on soleus motor neurones was evaluated from the monosynaptic Ia facilitation of the soleus H reflex evoked by femoral nerve stimulation. Femoral nerve facilitation was decreased at the onset of dorsiflexion and increased at the onset of plantar flexion in the healthy subjects and patients, but the changes were significantly greater in the healthy subjects. There was no difference between the two populations in the modulation of presynaptic inhibition during tonic plantar flexion and dorsiflexion. It is suggested that the abnormal regulation of disynaptic reciprocal inhibition and presynaptic inhibition in patients with spasticity is responsible for the abnormal modulation of stretch reflexes in relation to voluntary movement in these patients. Lack of an increase in reciprocal inhibition and presynaptic inhibition at the onset of dorsiflexion may be responsible for the tendency to elicitation of unwanted stretch reflex activity and co-contraction of antagonistic muscles in patients with spasticity.

Differential changes in corticospinal and Ia input to tibialis anterior and soleus motor neurones during voluntary contraction in man.

Motor-evoked potentials (MEPs) were recorded in the tibialis anterior and soleus muscles following transcranial magnetic stimulation (TMS) of the motor cortex. In the soleus, the H-reflex amplitude increased with the contraction level to the same extent as that of MEPs, whereas in the tibialis anterior, the H-reflex amplitude increased significantly less than that of MEPs. The latency of the MEPs decreased with contraction, whereas this was not the case of the H-reflexes. In the tibialis anterior, the response probability of single-motor units (SMU) to TMS increased more substantially during voluntary contraction than following stimulation of the peroneal nerve. In the tibialis anterior, the response probability of SMU increased more substantially during voluntary contraction than following stimulation of the peroneal nerve. The short-latency facilitation, presumably monosynaptic of origin, of the soleus H-reflex evoked by subthreshold TMS increased as a function of the plantarflexion force. This was not the case for the heteronymous Ia facilitation of the soleus H-reflex following stimulation of the femoral nerve. It is concluded that the corticospinal input to lower limb motor neurones generated by TMS increases with the level of voluntary contraction, whereas this is true only to a limited extent for the synaptic input from Ia afferents. It is suggested that this reflects changes in the susceptibility of corticospinal cells to TMS during voluntary contraction.

Beta 2-agonists for the treatment of wheezy bronchitis?

Nebulized albuterol (salbutamol) for the treatment of wheezy bronchitis was evaluated in a double-blind trial comprising 28 acutely ill children younger than 18 months and in 13 children 18 to 36 months of age. No significant difference in clinical effect was shown between albuterol and saline in the youngest group of children. Albuterol had some beneficial effect in children older than 18 months.

Respiratory infections in cystic fibrosis patients caused by virus, chlamydia and mycoplasma--possible synergism with Pseudomonas aeruginosa.

116 cystic fibrosis patients were observed, by monthly examinations over an eight-month period, to investigate the importance of non-bacterial respiratory infections (NBI) in exacerbations of the respiratory disease. Sputum was examined for bacteria, and serum investigated for antibody response against virus, mycoplasma and chlamydia and for antibodies against Pseudomonas aeruginosa. During this period each patient had, on an average, 2.9 exacerbations of which 76% were associated with bacteria, most frequently P. aeruginosa (51%), and 20% with NBI, although bacteria were also present in most of these cases. No etiology was established in 18% of the exacerbations. The NBI were caused by respiratory syncytial virus (RSV) (9%), parainfluenza virus (5%), influenza virus (3.6%), adenovirus (2.4%), mycoplasma (0.6%) and chlamydia (0.6%). The incidence of exacerbations was higher in patients with chronic P. aeruginosa infections. RSV infections were more common in patients who developed chronic P. aeruginosa infection during the study period, and RSV infections were frequently associated with a rise of P. aeruginosa antibodies in patients who harboured these bacteria. The important role of NBI as mediators of onset of chronic P. aeruginosa infections in cystic fibrosis patients is suggested.