Deep brain stimulation is associated with delayed improvement of parkinsonian symptoms, such as hypokinesia with subthalamic nucleus stimulation, or dystonia with globus pallidus internus stimulation. The latency observed is better explained by molecular alterations than immediate electrophysiological processes, and clinical improvement may involve adaptive gene expression. Here, we have studied immediate early gene expression as fast molecular response to subthalamic nucleus stimulation. Bipolar electrodes were implanted bilaterally into the subthalamic nucleus of anesthetized male Wistar rats. High-frequency stimulation (130Hz or 80Hz, 60μs, 300μA) or low-frequency stimulation (5Hz, 60μs, 300μA) was performed with the right electrode for 15, 60, 120, and 240 min whereas the silent left electrode served as negative control. Brains were fixed by transcardial perfusion and frozen sections were stained with polyclonal antibodies directed against three immediate early gene-encoded proteins, c-Fos, c-Jun, and Krox-24 (NGFI-A, Egr-1, Zif268, Tis8, Zenk). After 120 and 240 h, c-Fos immunoreactivity was strongly upregulated in subthalamic nucleus neurons on the stimulated site. In contrast, no c-Fos immunoreactivity was detected on the non-stimulated site except for single positive cells located in close proximity to the electrode tracks. Furthermore, c-Fos immunoreactivity was induced in subthalamic nucleus projection areas, such as primary and secondary motor cortex, primary somatosensory and insular cortex, lateral and medial globus pallidus, suprageniculate thalamic nucleus, pontine nuclei, medial geniculate nucleus, and substantia nigra. Similarly, c-Jun and Krox-24 were induced at the site of stimulation and in projection areas following high-frequency subthalamic nucleus stimulation. Whereas high frequency stimulation with 80Hz was similarly effective none of the three immediate early gene-encoded proteins was induced with low-frequency stimulation (5Hz) for 4 h. This is in accordance with the therapeutic effects of deep brain stimulation which are only elicited with high frequency stimulation. Our data provide evidence that immediate early gene expression in the subthalamic nucleus is rapidly and substantially induced by high-frequency stimulation. The induction of immediate early genes in projection sites suggests ipsilateral transsynaptic modulation of neuronal activity.

Motor outcome following stroke of the internal capsule is variable and its determinants are poorly understood. While many patients fully regain their abilities, recovery of motor functions remains incomplete in others. We analysed functional motor tasks of the upper limb to determine the pattern of focal disability after a small infarct of the internal capsule ('pure motor stroke') in the chronic stage (mean 2.4 years after stroke) with kinematic recordings of a reaching-to-grasp movement, with a quantitative analysis of the precision grip, and with clinical rating scales. The location of the lesions within the posterior limb of the internal capsule (PLIC) in 18 patients was determined from neuroimages obtained in the acute stage (5-20 days after the insult). Involvement of the PLIC was assessed at the level of the basal ganglia, approximately 8 mm above the anterior commissure-posterior commissure level. The distance between the posterior edge of the internal capsule and the centre of gravity of the lesion was determined. Chronic disabilities affected dextrous movements, while paresis was mild and sensitivity for light touch or passive finger flexion was almost normal. For both the reaching-to-grasp movement and the precision grip paradigm, the slowness of movement or force development was confined to the phases when grip formation and stabilization occur, while the onset of hand transport and of the vertical lifting force were not delayed. Grip forces were increased. We observed a close correlation between posterior location within the PLIC and the altered measures of timing and precision grip force. The more posterior the acute lesion was located within the PLIC, the more pronounced were the chronic motor deficits, as seen both in the quantitative measures and in the rating scales. The present study demonstrates for the first time that the amount and quality of chronic motor deficits of dextrous movements are related to a simple measure drawn from routine neuroimaging in the acute stage in patients with capsular stroke. The poor motor outcome in lesions involving the most posterior parts of the PLIC could be due to the condensed organization of corticofugal projections and the density of pyramidal fibres from the primary motor cortex in this subsector. Even small infarcts of this strategic area can disrupt many of the projections from the motor cortices and could thereby limit recovery strategies between homolateral motor representations.

Background: Recent animal experiments suggest an important role of descending input from basal ganglia to brainstem and via the reticulospinal tract (RST) to spinal cord in the genesis of motor symptoms in Parkinson disease (PD). In humans, a marker for RST activity is Ib mediated autogenic inhibition, which is reduced in PD patients. The authors investigated the effect of high frequency stimulation of the subthalamic nucleus (STN-HFS) on autogenic inhibition in PD. Methods: In 10 controls and 10 PD patients with chronically implanted STN electrodes, the soleus H-reflex conditioned by gastrocnemius nerve stimulation (interstimulus interval 2 to 10 msec) was used to examine the effect of STN-HFS on the activity of Ib spinal interneurons. Results: STN-HFS was able to restore the abnormally reduced autogenic inhibition. The H-reflex changes during STN-HFS significantly correlated with the clinical improvement of gait and posture. Conclusions: Observed changes in spinal autogenic inhibition may allow measurement of the contribution of subcortical routes to the STN-HFS induced motor benefit in PD.

Deep brain stimulation of the subthalamic nucleus (STN‐DBS) reduces akinesia in Parkinson's disease but its impact on fine motor functions was unknown. We assessed the effects of DBS and a levodopa (L‐dopa) test on the timing of the precision grip in 18 patients. Improvement on UPDRS‐items reflecting hand functions and the shortening of the first phases of the precision grip were more distinct in the L‐dopa test than in the pure STN‐DBS condition. Other akinesia items and the time for build‐up of lifting force were equally improved in both conditions. This suggests that routine STN‐DBS might not be equally effective on all aspects of fine motor functions. © 2003 Movement Disorder Society

The aim of this study was to characterize impairments of hand function in individuals with myelomeningocele (MMC) using a quantitative method. A grip‐lift task was studied in 29 individuals with MMC (17 females, 12 males; mean age 12 years 4 months, SD 5 years 6 months; range 4 to 28 years) and 29 age‐ and sex‐matched control participants. A small object (weight 200g) was grasped and lifted with a precision grip of the dominant hand and grip forces (GF) and time intervals were measured. Sensibility was examined with a two‐point discrimination test. In those with MMC, the latency between GF onset of the thumb and index finger and ensuing preload duration were both significantly prolonged (p<0.01). Fingertip forces were excessively high and variable. Several parameters differed significantly between those with MMC and control individuals: GF peak, GF at start of loading, mean GF, and the SDs of the GF during static holding. Although the two‐point discrimination task indicated deficits of sensibility, these did not correlate with grip force parameters. Results demonstrate that fine motor skills in patients with MMC are impeded by slowness and inadequate adjustments of manipulative forces.

OBJECTIVES Comparative gait analyses in neurological diseases interfering with locomotion are of particular interest, as many hypokinetic gait disorders have the same main features. The aim of the present study was (1) to compare the gait disturbance in normal pressure hydrocephalus and Parkinson's disease; (2) to evaluate which variables of the disturbed gait pattern respond to specific treatment in both diseases; and (3) to assess the responsiveness to visual and acoustic cues for gait improvement. METHODS In study 1 gait analysis was carried out on 11 patients with normal pressure hydrocephalus, 10 patients with Parkinson's disease, and 12 age matched healthy control subjects, on a walkway and on a treadmill. In study 2, patients with normal pressure hydrocephalus were reinvestigated after removal of 30 ml CSF, and patients with Parkinson's disease after administration of 150 mg levodopa. In part 3 visual cues were provided as stripes fixed on the walkway and acoustic cues as beats of a metronome. RESULTS The gait disorder in both diseases shared the feature of a reduced gait velocity, due to a diminished and highly variable stride length. Specific features of the gait disturbance in normal pressure hydrocephalus were a broad based gait pattern with outward rotated feet and a diminished height of the steps. After treatment in both diseases, the speed increased, due to an enlarged stride length, now presenting a lower variability. All other gait variables remained unaffected. External cues only mildly improved gait in normal pressure hydrocephalus, whereas they were highly effective in raising the stride length and cadence in Parkinson's disease. CONCLUSION The gait pattern in normal pressure hydrocephalus is clearly distinguishable from the gait of Parkinson's disease. As well as the basal ganglia output connections, other pathways and structures most likely in the frontal lobes are responsible for the gait pattern and especially the disturbed dynamic equilibrium in normal pressure hydrocephalus. Hypokinesia and its responsiveness to external cues in both diseases are assumed to be an expression of a disturbed motor planning.

OBJECTIVES:Normal pressure hydrocephalus (NPH) is an often underestimated cause of hypokinetic gait disorders in the elderly. Diagnosing NPH is a complex problem, since many symptoms overlap with other neurological diseases. The purpose of the present study was to characterize the gait pattern in NPH quantitatively. Additionally, we analyzed the improvement of gait parameters following tapping of cerebrospinal fluid (CSF).METHODS:Gait analysis was performed in 10 patients and 12 age-matched healthy controls during overground and treadmill locomotion.RESULTS:Compared to healthy controls, patients with NPH walked significantly slower, with shorter and more variable strides and a somewhat lower cadence. The feet were not lifted to a normal height and the dorsal extension of the forefoot prior to heel-strike was insufficient. Balance-related gait parameters such as step width and the foot rotation angles were significantly increased in NPH, while their variability was lower. Only some gait parameters improved after tapping 30 ml CSF. Gait velocity increased by about 23% due to an increased stride length, while the cadence remained unchanged. Balance-related gait parameters and the foot-to-floor clearance during swing were not affected by the treatment.CONCLUSIONS:In conclusion, we found a triad of decreased stride length, decreased foot-to-floor clearance and a broad-based gait to be the typical features of the gait abnormality in NPH. Only the stride length improved following a diagnostic spinal tap. These results may help to more reliably diagnose the condition of NPH in a routine clinical setting.

The aim of this study was to quantify the tremor of the hand during a natural movement (kinetic tremor) in tremor-dominant parkinsonian patients (n = 13). We used a three-dimensional camera system to kinematically analyze rest and kinetic tremors in an unrestrained reach-to-grasp movement, and additional tremor recordings were performed under standard postural and rest conditions using electromyography and accelerometry. The standard analysis showed a highly synchronized tremor with similar frequencies at rest and in sustained postural tasks, with and without loading. A kinematic recording was used to compare rest and action conditions. A strong inhibition of the resting tremor was present at the onset of the movement and reached its peak during deceleration. A kinetic tremor of low amplitude was present in most of the parkinsonian patients, but its occurrence was confined mainly to the terminal periods of the movement. The frequency of kinetic tremor was significantly higher than that at rest, before the onset of the movement in Parkinson's disease, as determined by the kinematic analysis (mean, 5.5 Hz vs 6.5 Hz; p <0.01). Our results confirm similarities between the tremor at rest and the oscillations during a sustained postural task in classic parkinsonian tremor. In contrast to this stable tremor, which seems to be generated by basal ganglia oscillators, a different pathophysiology of oscillations during motion must be considered. The kinetic tremor is most likely related to an enhancement of the physiologic tremor in the terminal phase of the reach-to-grasp movement.

We have used a three-dimensional X-ray cinematographic approach to investigate the kinematics of the forelimb during target reaching and food taking in five cats. Measurements of the trajectory of the limb during the reaching movement showed that the movement paths of the metacarpophalangeal joint (MCP) and the wrist were sigmoidal with a long nearly linear segment. The elbow followed a bent movement path with maximal inflection in the middle. The path of the humerus had an ascending parabola-like characteristic. The velocity profiles of the MCP and wrist were nearly bell-shaped and skewed to the left, whereas the profiles of the elbow joint were more or less double peaked with the second peak occurring 60-40 ms before object contact. Several different velocity peaks reflecting specific aspects of the task existed when the bell-shaped velocity profiles were divided in their vectorial components. Angular motion of the elbow consisted of a flexion-extension sequence during the reach and a flexion during the subsequent retraction. After an initial flexion during lift-off the wrist was extended. It kept this extended position during orienting towards the food container. During the retraction phase it was further extended. The angle between the wrist axis and the parasagittal plane changed during the movement. It first increased, then decreased during the last 100 ms before the object was reached. During the retraction it increased again to support the object weight against gravity. The position of the wrist was established by radio-ulnar supination and movements of the whole arm around the shoulder joint. We hypothesize that the position of the wrist axis is the controlled variable during protraction and retraction, regardless of whether it is achieved by radio-ulnar supination or by movements around the shoulder.

The maturation of manual dexterity and other sensorimotor functions was assessed with various behavioural tests. In healthy children (age 4–5 years) and in adults, the kinematics of reaching and grasping, a bimanual task and fast repetitive tapping movements were analysed. Furthermore a comprehensive motor function score (MOT), probing agility and balance, was evaluated. In the prehension task, the straightness of the reaching trajectories increased with age. Children opened their grip relatively wider than adults, thus grasping with a higher safety margin. The speed of both tapping and bimanual movements increased with age, and higher scores were reached in the MOT. Although the different behavioural tests sensitively indicated maturational changes, their results were generally not correlated, i.e. the outcome of a particular test could not predict the results of other tasks. Hence there is no simple and uniform relationship between different behavioural data describing maturation of sensorimotor functions.

Whereas a large body of data is available on the control of hand motoneurones from the brain, not much is known about the contribution of the spinal interneuronal apparatus to the differentiated movement repertoire of the hand. This review summarises recent data on the excitatory Ia pathways and on recurrent inhibition for cats, monkeys and humans. The basic principles of organisation have, in general, been preserved in the different species. Thus the motoneurones to cat and human long and short digit muscles seem not to possess a recurrent axon collateral system. With regard to the Ia pathways, specialised connectivity patterns have developed in the long digit extensor and wrist extensor muscles. They allow the former group to support the differentiated movement repertoire of the digits, and the latter group to be part of a general extensor or flexor synergism. Modifications between the species are present, however, with regard to the proximodistal connectivity across the elbow. Whereas they are regularly present in the cat, they are less developed in the monkey and absent in man, which frees the human hand from the elbow position.

1. The study aimed to describe in cat forelimb and shoulder motoneurones the convergence and projection patterns from large muscle spindle afferents (Ia). In 11 chloralose-anaesthetized cats maximum Ia EPSPs evoked by electrical stimulation of ipsilateral forelimb nerves were obtained in 309 intracellularly recorded alpha-motoneurones. 2. Groups of motor nuclei displayed similar Ia patterns. As in the distal forelimb they were often interconnected by bidirectional pathways, which were used to combine Ia synergistic groups. Three such groups are described at the shoulder. 3. The first group was composed of the main flexors of the scapulo-humeral joint. Regular disto-proximal Ia excitation from elbow extensors (and median afferents) indicates a coupling of flexion in the scapulo-humeral joint to the angular position of the elbow. 4. The second group comprised the outward rotators of the humerus with differentiated Ia convergence onto the different group members. The patterns of Ia excitation received and sent by the group members demonstrate that the outward rotators are incorporated in versatile synergisms and may occupy a central position in steering forelimb movements. 5. The third group was formed by the spinatus muscle and the subscapularis. This arrangement is suggested by the common convergence onto them from the elbow extensors and flexors. The pattern may serve to guide and keep the humeral head in the joint capsule. 6. The Ia synergistic groups receive Ia convergence from muscles acting at distant joints and also project to distant muscles. This is discussed as part of an extended pattern of Ia connections along the forelimb. In this way the shoulder muscles would be incorporated in flexor and extensor oriented synergisms which are needed to co-ordinate the muscular activation along the multijoint forelimb during locomotion. When the shoulder Ia pathways are compared with those in the distal forelimb, organization of the Ia system apparently follows a few basic principles which have adapted to the mechanical situation at the particular joints and their mechanical interaction.

To evaluate the normal development of functional hand motor skill, the kinematics of prehension movements were analyzed in 54 healthy children (age 4–12 years). The subjects repeatedly reached out for cylindrical target objects and grasped them with a precision grip of their dominant hand. The trajectory of the reaching hand and the finger aperture were monitored by optoelectronic motion analysis. To obtain comparable conditions for the different age groups, the experimental setup was scaled according to the individual body proportions of each subject. Within the investigated age range, neither the movement duration nor the normalized (according to body proportions) peak spatial velocity of the reaching hand changed significantly. However, the hand trajectory straightened and the coordination between hand transport and grip formation improved, resulting in smooth and stereotyped kinematic profiles at the age of 12 years. The younger children opened their grip relatively wider than the older ones, thus grasping with a higher safety margin. The dependence on visual control of the movement declined during motor development. Only the oldest childen were able to scale the grip aperture adequately, according to various sizes of the target objects, when visual control of the movement was lacking. The results suggest that the development of prehensile skills during childhood lasts until the end of the first decade of life. This functional maturation is discussed in relation to the development of neuronal pathways.

1. Synaptic responses to electrical stimulation of the contralateral pyramidal tract were measured in intracellular recordings from 206 upper limb motoneurones in ten chloralose-anaesthetized macaque monkeys. The objective was to search for evidence of a disynaptic excitatory pathway via C3-C4 propriospinal interneurones similar to that in the cat. 2. In monkeys with intact spinal cords, only a small proportion of motoneurones (19%) responded with late EPSPs to repetitive stimulation of the pyramid; only 3% had segmental latencies that were appropriate for a disynaptic pathway. 3. From previous studies in the cat, it was expected that a lesion to the dorsolateral funiculus (DLF) at C5 would interrupt the corticospinal input to the spinal segments supplying upper limb muscles, whilst leaving intact excitation transmitted via a C3-C4 propriospinal system, the descending axons of which travel in the ventral part of the funiculus. In five of the monkeys a lesion was made to the DLF at C5 which spared the ventrolateral columns. It severely reduced the monosynaptic EPSPs and disynaptic IPSPs evoked from the pyramidal tract that were present in the intact monkey spinal cord, and which might have masked the presence of disynaptic EPSPs. However, even after the lesion the proportion of motoneurones with such late EPSPs was still low (18%); 14% of motoneurones had EPSPs within the disynaptic range. 4. In addition, some EPSPs with relatively long segmental latencies (> 1.1 ms) were recorded before and after the C5 lesions, but since these effects could be evoked by single stimuli, had stable latencies and did not facilitate with repetitive shocks, it is likely that they represent monosynaptic EPSPs evoked by slowly conducting corticospinal fibres which survived the lesions. 5. In seven of the monkeys motoneurone responses to stimulation of the ipsilateral lateral reticular nucleus (LRN) were also tested. Most motoneurones showed EPSPs with short latencies (1.2-2.5 ms) and other properties characteristic of monosynaptic activation. This is consistent with the presence of collaterals of C3-C4 propriospinal neurones to the LRN, as demonstrated in the cat. 6. These short-latency EPSPs evoked from the LRN were just as common before (77%) as after (75%) the C5 lesion. They had small amplitudes both before (mean +/- s.d. 1.1 +/- 0.59 mV) and after (1.2 +/- 0.72 mV) the lesion. Unlike the situation in the cat, only a small proportion (16%) of motoneurones activated from the LRN showed late EPSPs after repetitive stimulation of the pyramid. 7. The results provide little evidence for significant corticospinal excitation of motoneurones via a system of C3-C4 propriospinal neurones in the monkey. The general absence of responses mediated by such a system in the macaque, under experimental conditions similar to those in which they are seen in the cat, show that extrapolation of results from the cat to the primate should be made with considerable caution.

The recovery of motor functions after CNS lesions is a complex action with several restitutional processes occurring in parallel. To describe the function-oriented phenomena and to understand the organisational changes within the neuronal systems in question there is the urgent need for investigations relating the impairment of defined neuronal systems with quantitative and qualitative changes of a behavioural motor paradigm. The system of the C3-C4 propriospinal neurones in the cat is one of the models which could serve such a purpose. It relays disynaptic excitation from several supraspinal motor centres to forelimb motoneurones, parallel to the input to the motoneurones from the same centres via the segmental reflex apparatus. Behavioural studies indicate that the motor command for reaching towards a target with the forelimb is to a large extent mediated in the C3-C4 propriospinal system, whereas the command for taking of the object seems to be organised in the interneuronal systems of the forelimb segments, not depending on an integration in the C3-C4 propriospinal relay. The paper reviews different studies which have analysed the effects of lesions of various motor centres and tracts on this behavioural paradigm. It becomes evident that different components of the motor behaviour have different restitutional capacities. The quantitative analysis of the various dimensions of the cat forelimb together with the possibility to perform localised lesions within defined neuronal systems make this experimental approach suited for the investigation of integrative aspects related to the restitution of function within systems organising motor behaviour.

The kinematics of the cat distal forelimb during food-taking were analysed to obtain information on the movement processes within the paw before and during object taking in a species without monosynaptic corticomotoneuronal projections. The behaviour was investigated with two tests: either the table test (TT, food offered on a table located at ground level in a reaching distance of 22 and 28 cm) or the horizontal test (HT, food offered in a small container located at shoulder level, height 18-25 cm, reaching distance 6-12 cm). In five animals, the changes in configuration and the conjoint actions of the wrist, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints were assessed with three-dimensional X-ray cinematography (time resolution 20 ms, spatial resolution 1 mm) and video analysis. While approaching the target, the digits were first extended and subsequently abducted. This 'preshaping' consisted of combined angular changes in the MCP and PIP joints, thereby attaining an adequate grip aperture. Each cat used a stable strategy, but different cats used different strategies. In the TT, preshaping involved an MCP extension and a PIP flexion. In the HT, predominant extension of the MCP, predominant extension of the PIP, or a combination of both were used, followed by MCP flexion and PIP flexion. The grip aperture started to decrease before object contact, earlier in the TT, later in the HT. Grasping was achieved by flexion of first the PIP and later the MCP. The X-ray analysis gave evidence for individuated digit movements. Correlation analysis of the angular position of the joints between the different phalanges showed that digits 3 and 4 acted in concert, as did digits 2 and 5, but with clear independence between the different pairs. Furthermore, the different phalanges served different purposes during the grasp. Digits 3, 4 established object contact, digits 2, 5 were mainly used to stabilize the paw onto the surface. The cat distal forelimb displays a refined movement repertoire during the preshaping and grasping phase of food-taking. During the preshaping phase, the kinematics resembled in some aspects the situation in humans. The results demonstrate the ability of the polysynaptic projections from the cortico-motoneuronal system to organize differentiated distal limb movements, including individuated movements of the digits.