J A Obeso

Missing pieces in the Parkinson's disease puzzle

Parkinsons disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.

THE FUNCTION OF THE ANTAGONIST MUSCLE DURING FAST LIMB MOVEMENTS IN MAN

We have examined fast flexion movements of the human thumb and fast extension movements of the elbow over three different distances at a variety of speeds in order to elucidate the function of the antagonist muscle in these circumstances. All movements were of such a velocity that they showed the typical bi‐ or triphasic pattern of muscle activation in agonist and antagonist. Slower movements, with continuous agonist activity, were not analysed. For movements made through the same angle at different velocities, there was a linear relationship between the amount of antagonist activity needed to halt the movement and the peak velocity. However, the slope of this relationship was a function of the distance moved. Movements made through large angles showed less antagonist activity than those made through small angles at the same speed. The timing of the antagonist activity also changed as a function of both distance and speed. Fast, small movements showed earlier onset of antagonist activity than slow, large ones. Movements which were halted mechanically with the subjects prior knowledge had little or no antagonist activity, since it was no longer necessary in these conditions. The complexity of these relations indicates that the triphasic pattern of muscle activity underlying these movements can no longer be regarded as a simple immutable ‘programme. The size and timing of the bursts of muscle activity are subtly adjusted to the precise nature of the task.

Reciprocal inhibition between the muscles of the human forearm.

Peripheral and central mechanisms of reciprocal inhibition between antagonist muscles in the forearm have been studied in ten human subjects. H reflexes were evoked in flexor muscles by stimulating the median nerve with single shocks at around motor threshold intensity. Peripheral inhibition of the flexor H reflex was produced by motor threshold stimulation with a single shock of the radial nerve supplying the extensor muscles. The conditioning radial nerve stimulus produced inhibition of the flexor H reflex consisting of three phases. In some individuals, an H reflex could be evoked in extensor muscles of the forearm. Stimulation of the median nerve produced inhibition of the extensor H reflex with a similar time course to that from extensors to flexors. The first phase of inhibition was apparent when the test median nerve shock was given from 1 ms before to 3 ms after the conditioning radial nerve shock. It was abrupt in onset and short in duration and could be evoked with a conditioning stimulus intensity as low as 0.75 X motor threshold. The second and third phases of inhibition were evident when the conditioning radial nerve stimulus preceded the median nerve test shock by 5 to 50, and 50 to 500 ms respectively. The characteristics of these later phases of inhibition are to be the subject of a separate report. The difference in timing of the peak initial short‐latency inhibition from extensor to flexor and from flexor to extensor muscles enabled an estimate to be made of the central synaptic delay of the inhibitory process. This method yielded a central delay of 0.95 ms in excess of that of the H reflex. We conclude that the first phase of inhibition is mediated via large group I afferents acting through a single inhibitory interneurone . Central inhibition of the flexor H reflex was demonstrated with the radial nerve anaesthetized by injection of local anaesthetic at the elbow. Subjects were asked to try to contract the paralysed extensor muscles. Under this condition, attempted voluntary wrist extension inhibited the flexor H reflex even though no movement occurred. A shock was delivered to the radial nerve at a site proximal to the anaesthetic block. When the shock was applied in conjunction with an attempted voluntary contraction of the paralysed extensor muscles, the depth of inhibition was greater than that predicted from the effect of either a shock or a willed contraction acting independently.(ABSTRACT TRUNCATED AT 400 WORDS)

The behaviour of the long-latency stretch reflex in patients with Parkinson's disease

The size of the long-latency stretch reflex was measured in a proximal (triceps) and distal (flexor pollicis longus) muscle in 47 patients with Parkinsons disease, and was compared with that seen in a group of 12 age-matched normal control subjects. The patients were classified clinically into four groups according to the degree of rigidity at the elbow or tremor. Stretch reflexes were evaluated while the subject was exerting a small force against a constant preload supplied by a torque motor, and the size of the reflex response was measured as fractional increase over basal levels of activity. When stretches were given at random intervals by increasing the force exerted by the motor by a factor of 2 or 3, there was a clear trend for the more severely affected patients to have larger long latency responses in the triceps muscle, although there was no change in the size of the short-latency, spinal component of the response. In contrast, there was no change in the size of the long-latency response of the flexor pollicis longus in any group of patients with Parkinsons disease. Despite any differences in reflex size, the inherent muscle stiffness of both muscles appeared to be normal in all groups of patients with Parkinsons disease, since the displacement trajectory of the limb following the force increase was the same as control values in the short (25 ms) period before reflex compensation could intervene. In 20 of the patients and in seven of the control subjects, servo-controlled, ramp positional disturbances were given to the thumb. Up to a velocity of 300°/s, the size of the long-latency stretch reflex was proportional to the log velocity of stretch. This technique revealed, in both moderately and severely rigid patients, increases in the reflex sensitivity of the flexor pollicis longus, which had not been clear using step torque stretches alone. However, whether using ramp or step displacements, long latency stretch reflex gain was not closely related to rigidity; reflex size was within the normal range in many patients with severe rigidity. Enhanced long latency stretch reflexes thus contribute to, but may not be solely responsible for, rigidity in Parkinsons disease.

Efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson's disease 4 years after surgery: double blind and open label evaluation.

Objective: To evaluate the long term (4 years) efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in advanced Parkinson’s disease. Methods: We performed a double blind crossover evaluation of the efficacy of DBS of the STN in the “off” medication condition in 10 patients with Parkinson’s disease. Assessments included the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (motor) and two timed tests (arm tapping and walking). Open evaluation of the effect of stimulation in the off and on drug states preoperatively and at 1 and 4 years postoperatively was also conducted. The latter assessment included the UPDRS parts II (activities of daily living) and III (dyskinesia scale and global assessment) as judged by the patient and examiner. The mean amount of levodopa daily dose at base line, 1 year, and 4 years after surgery was compared. Results: A significant (p<0.04) effect of stimulation was observed in the overall group regarding both the UPDRS motor and the timed tests. Open evaluation also showed a significant benefit of STN DBS with respect to preoperative assessment in both the motor and activities of daily living scales, dyskinesia scale, and in global assessment. Levodopa daily dose was reduced by 48% and 50% at 1 and 4 years, respectively. There was no difference between the 1 and 4 years evaluations in any of the parameters evaluated. Complications due to stimulation were minor. Conclusions: DBS of the STN provides a significant and persistent anti-parkinsonian effect in advanced Parkinson’s disease 4 years after surgery.

Impact of deep brain stimulation on upper limb akinesia in Parkinson's disease.

Recent pathophysiological models of Parkinsons disease have led to new surgical approaches to treatment including deep brain stimulation (DBS) and lesioning of basal ganglia structures. Various measures of upper limb akinesia were assessed in 6 patients with bilateral DBS of the internal pallidum and 6 with DBS of the subthalamic nucleus. Stimulation improved a number of aspects of motor function, and particularly movement time, and force production. Time to initiate movements, and to perform repetitive movements also improved but less dramatically. Processes indicating preparatory motor processes showed no significant change. Few significant differences were found between the internal pallidum and subthalamic nucleus groups. In general, the effects of DBS closely parallel previous reports of the effects of dopaminergic medication. It is suggested that disrupted pallidal output in Parkinsons disease interferes with the rate, level, and coordination of force production but has little effect on preparatory processes. The similarity of the effects of subthalamic nucleus and internal pallidum stimulation suggests this disrupted outflow is the most important determinant of upper limb akinesia in Parkinsons disease. The effects of DBS were similar to the effects of unilateral pallidal lesions reported elsewhere. Ann Neurol 1999;45:473–488

Simple tics in Gilles de la Tourette's syndrome are not prefaced by a normal premovement EEG potential.

EEG events prior to simple tics have been examined in six patients with Gilles de la Tourettes syndrome, and compared to EEG changes occurring when the same subjects voluntarily mimicked their own tics. Voluntary jerks were prefaced by a premovement negative potential commencing about 500 ms prior to the muscle EMG discharge and reaching an amplitude of about 7 muV. No such premovement potential was evident in the EEG prior to spontaneous tics in five of the six patients; a very small event was seen in the sixth patient but it was only about one-tenth of the size of the premovement potential seen prefacing voluntary jerks in the same subject. These data indicate that simple tics in Gilles de la Tourettes syndrome are physiologically distinct from normal self-paced willed movements.

The anatomical basis of somaesthetic temporal discrimination in humans.

Somaesthetic temporal discrimination (STD) is the ability to perceive as separate two successive somaesthetic stimuli applied to the same or different parts of the body. Paired electrical stimuli were applied to the index finger, using different time-intervals, to study the STD threshold (STDT) in 84 normal subjects and 51 patients with focal cerebral lesions. Abnormal STDT values were found on the affected side of patients with a lesion of the primary somatosensory cortex, and internal capsulethalamus. Lesions which did not produce sensory impairment but caused abnormal STDT were located in the posterior parietal cortex, the head of the caudate nucleus, the putamen, the medial thalamus and the lenticular nucleus. Frontal, temporal and occipital cortex lesions did not produce any abnormality in the STDT, but one patient with a bilateral lesion of the supplementary motor area (SMA) had abnormal STDT. These results indicate that normal perception of two somaesthetic stimuli as separate in time depends not only upon the integrity of the somatosensory pathway and primary somaesthetic cortex, but also of the posterior parietal cortex, SMA and subcortical structures such as the striatum and thalamus.

Selective neuronal vulnerability in Parkinson disease

Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.

On the significance of giant somatosensory evoked potentials in cortical myoclonus.

Four patients with cortical myoclonus were studied. All had reflex muscle jerking and grossly enlarged somatosensory evoked responses (SEPs) following electrical stimulation of the digital nerves. In addition, three of the patients had spontaneous or action-induced myoclonus. Back-averaging the EEG from these spontaneous muscle jerks showed a large positive wave over the contralateral somatomotor cortex which preceded the jerk by about 20 ms. Administration of lisuride (0.1 mg iv) reduced the severity of the reflex and spontaneous myoclonus, but had no effect on, or increased the size of the SEP. Two of the patients also received 1 mg clonazepam iv. As with lisuride, the severity of myoclonic jerking was reduced although the size of the SEP was increased. It is concluded that the usual association between giant SEPs and reflex muscle jerking can be abolished by acute administration of lisuride and clonazepam in patients with cortical myoclonus.