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Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 577 records · Page 32Linked to original sources
PubMed1987

The physiology of idiopathic dystonia.

Dystonia is mysterious and its pathophysiology is uncertain. The fundamental motor abnormality is an abnormality of muscle command signals, such that the wrong agonists may be activated for too long, there is abnormal co-contraction of agonist and antagonists, and there is excessive and misdirected action of synergists and postural fixators. The result is action dystonia. In addition, muscle spasms may occur spontaneously. The peripheral motor apparatus, the corticomotoneurone pathway, and (as far as is known) the proprioceptive feedback machinery, are all intact in primary dystonia. However, a defect of interneuronal machinery has been identified in both the brainstem and spinal cord. In blepharospasm there is hyperexcitability of the lower brainstem interneurones responsible for the R2 component of the blink reflex. In the dystonic arm there is loss of the later phases of Ia reciprocal inhibition from extensors to flexors. Both deficits may be due to loss of normal basal ganglia inputs onto interneurones. The known sites of focal lesions that may cause symptomatic dystonia all impair basal ganglia output. However, whether such abnormal interneuronal function is sufficient to explain dystonia is not known. Among many unanswered questions are 1) are the cortical instructions for movement specified correctly, and 2) what is responsible for the spontaneous dystonic spasms?

Dystonia↗
PubMed1987

Disturbance of sequential movements in patients with Parkinson's disease.

The following sequences of two single movements were examined in 10 patients with Parkinson's disease and compared with the performance of 9 normal subjects of similar age. Isometric opposition of thumb and fingers to a force of 30 N ('squeeze'), followed by isotonic elbow flexion ('flex') through 15 degrees with the same arm. 'Squeeze' with the left hand followed by 'flex' with the right elbow. Isotonic opposition of thumb and fingers ('cut') through 90 degrees followed by isotonic 'flex' with the same arm. Isotonic elbow 'flex' followed by isometric 'squeeze' with the same arm. All movements were self-paced. Subjects were given instructions to move as rapidly as possible and to start the second movement immediately after the end of the first. Patients were slower than normal when each single movement was performed separately. There was a further decrease in speed when two movements were executed sequentially. This was due to an increase in movement duration of each of the component movements, especially the second, and to an increase in the pause between the first and second movements. In both normals and patients, there was no correlation between the times taken to perform the first and second movements of any of the four sequences that were studied. Because of this we suggest that the two components of the sequence remained under the control of two separate motor programs. When performing the sequential tasks, normal subjects automatically chose an interval between the onsets of the two separate movements of about 230 ms, even in tasks in which the duration of the first movement was less than 200 ms. If normal subjects were instructed to begin the second movement with an interonset interval of less than 200 ms, the speed of the second movement was much slower. Patients with Parkinson's disease automatically chose a much longer interonset interval of 400-500 ms. In addition, they exhibited difficulty in switching from the first to the second movement in the sequence. We suggest that the problems exhibited by patients with Parkinson's disease when they try to perform two rapid sequential movements can be seen as a deficit in the capacity to switch from one motor program to another within an overall motor plan.

Adult↗
PubMed1987

Motor cortex stimulation in intact man. 1. General characteristics of EMG responses in different muscles.

This paper is the first of two papers describing our five-year experience with the technique of electrical stimulation of the human motor cortex. In this first paper we illustrate the basic distribution and behaviour of electromyographic responses in limb muscles to anodal stimulation of the motor cortex in intact, awake human subjects. These responses may be recorded at short latency, with estimates of conduction velocities from the brain to the spinal cord suggesting transmission in rapidly conducting pathways, such as the corticomotoneuronal component of the corticospinal tract. The site at which the stimulus activates these motor pathways to produce responses at such short latency is likely to be at, or adjacent to the origin of these major descending motor pathways in the cerebral cortex. The best stimulating sites for activation of arm or leg muscles corresponds to the known somatotopic arrangement of the cerebral cortex. The electromyographic response characteristics are different in the contracting, as compared with the relaxed muscle; the EMG response latency shortens, its size becomes larger and its threshold is lowered when the muscle is voluntarily made to contract. The mechanisms that are responsible for these characteristics are examined in the following paper.

Adult↗
PubMed1987

Motor cortex stimulation in intact man. 2. Multiple descending volleys.

Using an isometric strain gauge, we measured the twitch force produced in the first dorsal interosseous (FDI) muscle by a single anodal shock to the contralateral scalp. At high intensities of stimulation this twitch can greatly exceed the force produced by supramaximal stimulation of peripheral nerve. This indicates that a single cortical shock can cause repetitive firing of some or all FDI motoneurons. Such repetitive firing was demonstrated using a collision technique in which a supramaximal ulnar nerve stimulus was given at the wrist shortly after a cortical shock. The antidromic volley from the peripheral nerve stimulation failed to obliterate completely the response to cortical stimulation. Additional EMG activity was visible in the normally silent period between ulnar M and F waves. This activity must have been due to the presence of repetitive volleys of activity set up in spinal motoneurons by the cortical shock. Such activity summates with the twitch produced by the ulnar M wave to produce a very large force twitch of the muscle. Multiple firing of some motoneurons can be observed in some individuals at cortical stimulation intensities below that necessary to evoke activity in all the motoneurons in the FDI pool. Multiple firing probably was caused by repetitive excitatory inputs impinging on spinal motoneurons. These could be demonstrated using poststimulus time histogram techniques on single motor units. Low intensities of cortical stimulation produced a single short duration (mean 1.8 ms) peak of increased motor unit firing 20 to 30 ms after the shock. At high intensities, this was followed by extra peaks some 4 to 5 ms later. H reflex testing showed that the threshold of the initial descending volley, produced by the cortical stimulus was uninfluenced by a voluntary contraction. These results are discussed with reference to the D and I waves recorded from pyramidal tract after anodal stimulation of the exposed cortex in animals.

Biomechanical Phenomena↗
PubMed1987

Some experiences of techniques for stimulation of the human cerebral motor cortex through the scalp.

Stimulation of the motor cortex transcranially has shown a rough somatotopy of stimulation sites on the scalp corresponding to the homunculus and preferential activation of contralateral hand muscles, as well as very short latencies of signals in the cervical spinal cord. The responses are also facilitated by background activation of the muscles. We are reporting a set of patients studied using electrical and magnetic stimulation transcranially. We observed that the latency of electromyogram activation is much shorter in active than contracting muscles and that the muscle twitch produced by cortical stimulation can exceed the force produced by supramaximal stimulation of the peripheral nerve. Our findings suggest that this may be due to multiple firing of motor neurons. Another observation is that magnetic stimulation is not as subject to a reduction in the response latency with facilitation, and response latencies with magnetic stimulation were 2 ms longer than with electrical stimulation. The implications of these findings are discussed.

Adult↗
PubMed1987

Pharmacological characterization of binding sites identified in rat brain following in vivo administration of [3H]-spiperone.

[3H]-spiperone is commonly used to label dopamine receptors in vitro in brain tissue. However, spiperone also interacts with brain 5-hydroxytryptamine and noradrenaline receptors. In vivo, [3H]-spiperone has been used for identifying dopamine receptors in both animals and man but the nature of the sites identified is unknown. The in vivo administration of [3H]-spiperone to rats leads to a selective accumulation of radioactivity in the olfactory lobes, tuberculum olfactorium, nucleus accumbens, striatum, substantia nigra, hippocampus, frontal cortex and hypothalamus, when compared to the cerebellum. In vivo drug displacement studies suggest that the binding of [3H]-spiperone in these areas may be to dopamine, 5-HT or noradrenaline receptors. [3H]-spiperone in vivo mainly labels dopamine receptors in striatum, tuberculum olfactorium, hypothalamus, substantia nigra and olfactory lobes. However, in the frontal cortex and nucleus accumbens specific binding involves not only dopamine receptors but also 5-HT and/or noradrenaline receptors. Interpretation of in vivo studies in man using radioactive spiperone and its derivatives must take into account the fact that this ligand only labels dopamine receptors in some brain areas.

Animals↗
PubMed1987

L-dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease.

Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice. The 2-tetrahydropyranylmethyl, 2-(1-methoxy)propyl, 2-hydroxypropyl, n-propyl, benzyl and phenoxyethyl ester prodrugs produced effects comparable with those of L-dopa. In contrast, the cyclohexyl, m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs were less effective than L-dopa on oral administration. Intraperitoneal administration of L-dopa and the ester prodrugs of L-dopa to rats with a prior 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB) produced contraversive circling responses. Rotation observed following administration of the n-propyl, 2-tetrahydropyranylmethyl, methyl and ethyl ester prodrugs was more intense than that observed following administration of L-dopa itself. Rotation produced by the administration of L-dopa and the cyclohexyl, 2-(1-methoxy)propyl, phenylethyl, p-chlorophenylethyl, p-methoxyphenylethyl, benzyl, 2-hydroxypropyl, phenoxyethyl and m-trifluoromethylbenzyl ester prodrugs was identical. Ester prodrugs of L-dopa may be as effective as L-dopa itself in producing motor activity but overall none of the compounds tested was markedly more potent or of longer duration than L-dopa itself.

Animals↗
PubMed1987

L-dopa esters as potential prodrugs: effect on brain concentration of dopamine metabolites in reserpinized mice.

The intraperitoneal administration of L-dopa and a series of ester prodrugs of L-dopa to reserpinized mice produced elevations of striatal and tuberculum olfactorium homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Differences in the pattern of change produced by individual drugs, compared with L-dopa, were observed. Only the phenoxyethyl ester caused elevations of both striatal and tuberculum olfactorium HVA and DOPAC, greater than those measured following L-dopa administration. Overall the m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs produced greater elevations of striatal and tuberculum olfactorium HVA, but not DOPAC, compared with L-dopa. The administration of the 2-tetrahydropyranyl-methyl derivative only enhanced striatal HVA and striatal and tuberculum olfactorium DOPAC concentrations. Changes of HVA and DOPAC tissue concentrations following administration of the 2-hydroxypropyl, n-propyl, methyl, ethyl and 2-(1-methoxy)propyl ester prodrugs were comparable with those produced by the administration of L-dopa itself. The alterations in striatal and tuberculum olfactorium HVA and DOPAC levels observed did not correlate with the ability of these compounds to elicit locomotor activity in reserpinized mice.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Comparison of changes in locomotor activity with striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations following the bilateral intranigral injection of dopamine agonist drugs in rats.

Bilateral injection of apomorphine (2.5 micrograms) into the substantia nigra zona reticulata of rats reduced both locomotor activity and striatal HVA and DOPAC concentrations. Bilateral injection of dopamine (10 micrograms) did not affect locomotor activity whereas a higher dose of dopamine (50 micrograms) enhanced locomotor activity. Striatal HVA and DOPAC concentrations were unchanged following injection of dopamine. Bilateral injection of (+/-)-3PPP (0.1 or 2.5 micrograms) into the zona reticulata of the substantia nigra did not alter locomotor activity while a higher dose (10 micrograms) enhanced locomotion. Injection of (+/-)-3PPP (0.1-10 micrograms) into the zona reticulata was without effect on striatal HVA or DOPAC concentrations. The bilateral manipulation of nigral dopaminergic neurotransmission alters motor activity and nigrostriatal dopamine turnover in conscious rats. However, the changes in motor activity are not necessarily related to altered nigrostriatal activity, suggesting the involvement of dopamine receptors located at non-dopaminergic sites within the substantia nigra.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Evidence favouring presynaptic inhibition between antagonist muscle afferents in the human forearm.

1. A single motor-threshold electrical stimulus to the radial nerve in the spiral groove produced three phases of inhibition in the H reflex of relaxed wrist and finger flexor muscles. The first phase of inhibition occurred with a conditioning-test interval of -1 to 3 ms and represents disynaptic Ia reciprocal inhibition of flexor motoneurones by afferent input from extensor muscles. The second phase occurred with a conditioning-test interval of 5-40 ms. The characteristics of the second inhibitory phase have been investigated in the present study. 2. The threshold intensity of radial nerve stimulation required to produce the second phase of inhibition was 0.7 X motor threshold and was the same as that required to produce the first (disynaptic) phase of inhibition. 3. The time course of the effect of a radial nerve stimulus on the size of e.m.g. response to transcranial electrical stimulation of the motor cortex also was studied. The results were compared to those obtained with H reflex testing. The time course and depth of the first phase of inhibition were identical with both test inputs. The second phase of inhibition, however, was seen only with the H reflex test stimulus. When the corticospinal volley was timed to arrive at the cervical cord 30 ms after the radial nerve afferent volley, the flexor muscle response was facilitated rather than inhibited. 4. A single stimulus (2-3 X sensory threshold) to the superficial (cutaneous) branch of the radial nerve at the wrist failed to produce inhibition of the flexor H reflex. Instead, the H reflex was facilitated when the median nerve Ia volley (for the H reflex) was timed to arrive at the cervical cord between 30-40 ms after the radial nerve cutaneous afferent volley. In contrast to results using mixed nerve stimulation in the spiral groove, there was no difference between the effect of this cutaneous input on the cortically evoked e.m.g. response and the H reflex. 5. We conclude that the second phase of flexor H reflex inhibition is produced by activity in large-diameter (group I) extensor muscle afferents which acts on the H reflex pathway at a premotoneuronal site.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1987

Olfactory threshold in Parkinson's disease.

Olfactory threshold to differing concentrations of amyl acetate was determined in 78 subjects with idiopathic Parkinson's disease and 40 age-matched controls. Impaired olfactory threshold (previously reported by others) was confirmed in Parkinsonian subjects compared with controls. There was no significant correlation between olfactory threshold and age, sex, duration of disease, or current therapy with levodopa or anticholinergic drugs. In a sub-group of 14 levodopa-treated patients with severe "on-off" fluctuations, no change in olfactory threshold between the two states was demonstrable. Olfactory impairment in Parkinson's disease may involve mechanisms that are not influenced by pharmacologic manipulation of dopaminergic or cholinergic status.

Adult↗
PubMed1987

Simple and complex movements off and on treatment in patients with Parkinson's disease.

The performance of a 15 degrees elbow flexion and a 30N hand squeeze was studied in nine normal subjects and in five patients with Parkinson's disease. The patients were studied when immobile after 12-18 hours withdrawal from antiparkinsonian drug therapy (OFF) and when more mobile after drugs (ON). Subjects performed each movement separately (simple movements) and both movements either simultaneously or sequentially (complex movements). The duration of both movements and the time between the onset of each movement in the sequential task (interonset latency) were measured. The patients OFF therapy had longer movement times than normal for both movements; these improved after levodopa but still were not normal. When the patients performed complex movements there was an extra slowness, over and above that seen for simple movements, in both movements of the simultaneous task and in the second movement of the sequential task. In addition, the interonset latency in the sequential task was longer than normal. After levodopa there was a more striking improvement in the movement times of complex movements than there had been for simple movements. The interonset latency in the sequential task was shorter than before therapy though still was not the same as in normal subjects. It is suggested that the basal ganglia are not only involved in the execution of simple motor programmes, but also play some role in the superimposition and sequencing of motor programmes.

Adult↗
PubMed1987

Single-dose pharmacokinetics of Madopar HBS in patients and effect of food and antacid on the absorption of Madopar HBS in volunteers.

Pharmacokinetic studies in parkinsonian patients and healthy volunteers have shown that Madopar HBS behaves as a slow-release formulation of L-dopa and benserazide. In comparison with standard Madopar the rate of absorption is reduced, providing lower peak concentrations of L-dopa. The drug is released and absorbed over a period of 4-5 h, thus maintaining substantial plasma concentrations for 6-8 h after dosing. Although the bioavailability after oral dosing is reduced as compared with standard Madopar (60-70%), this difference seems to be due to incomplete absorption rather than altered disposition of the drug. The presence or absence of food in the stomach has no effect on the absorption of L-dopa from Madopar HBS, but administration of antacids further reduces the bioavailability (45%).

Adult↗
PubMed1987

Single-dose studies of a slow-release preparation of levodopa and benserazide (Madopar HBS) in Parkinson's disease.

The clinical effects and pharmacokinetic profiles of single doses of Madopar HBS were compared with those of standard Madopar in two studies in patients with Parkinson's disease and 'on-off' fluctuations. In the first study, 10 fasting patients received equivalent doses (200 mg levodopa plus 50 mg benserazide) of each preparation. The clinical response to Madopar HBS was delayed and brief; the relative bioavailability was only 50%. In the second study in 7 non-fasted patients, the effects of 3 capsules of Madopar HBS 125 were compared with those of 2 capsules of standard Madopar 125. Delay to turn on was longer with HBS, but duration of time on, and delay to turn off, were longer with this preparation. The area under the concentration-time curve for plasma levodopa was greater with HBS, and the maximum levodopa concentration was similar to, but achieved later than standard Madopar.

Administration, Oral↗
PubMed1987

Open study of Madopar HBS, a new formulation of levodopa with benserazide, in 13 patients with Parkinson's disease and 'on-off' fluctuations.

In a open study in 13 patients with Parkinson's disease with 'on-off' fluctuations, all (n = 3) or part (n = 10) of the usual intake of levodopa (with peripheral decarboxylase inhibitor) was replaced by Madopar HBS for 5-122 days (median 35). Time 'off' increased in 2 of the 3 monotherapy subjects. With combined therapy, time 'on' was increased in 6, unchanged in 2 and reduced in 2. However, 11 of the 13 patients complained of reduced predictability of clinical response with Madopar HBS. Only 4 of the 13 patients preferred to continue with combined standard plus HBS treatment; this continued treatment led to an increase in time 'on' in 3 and a decrease in involuntary movements in 3 patients. Two of these four patients benefited on both counts.

Adult↗