Low-frequency versus high-frequency stimulation of the pedunculopontine nucleus area in Parkinson's disease: a randomised controlled trial.

OBJECTIVE: To compare the influence of low-frequency (10-25 Hz) versus higher (60-80 Hz) frequency stimulation of the pedunculopontine nucleus area (PPNa) on akinaesia, freezing of gait and daytime sleepiness. METHOD: We included nine patients with Parkinson's disease (PD) and severe gait disorders. In this double-blind randomised cross-over study, patients were assessed after 24 h of PPNa stimulation. Assessments included the motor part of the Unified Parkinson's Disease Rating Scale, the Epworth Sleepiness Scale and a behavioural gait assessment. RESULTS: Compared with 60-80 Hz, 10-25 Hz PPNa stimulation led to decreased akinaesia, gait difficulties and daytime sleepiness in 7/9 patients. In one patient, these symptoms were aggravated under 10-25 Hz stimulation compared with 60-80 Hz. CONCLUSION: These results are in keeping with the benefits of chronic PPNa stimulation for gait and postural difficulties in patients with PD, and with regard to the influence of patients' clinical characteristics, differential neuronal loss in the PPNa and electrode location. We conclude that in patients with PPNa stimulation, low frequency provides a better outcome than high-frequency stimulation.

Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease.

We examined executive functioning in patients with Parkinson's disease exhibiting, or not, levodopa-resistant freezing of gait (L-FOG). 38 advanced-stage patients with L-FOG were identified in a consecutive series of 400 patients. They were matched with 38 patients without L-FOG. All patients underwent prospective evaluations of cognitive and motor functioning before subthalamic nucleus surgery, and 1 year after. A composite frontal score, a measure of executive functioning, was compared between the two groups. We also examined correlations between the frontal score and the score on the FOG item of the Unified Parkinson Disease Rating Scale II. Results show that after surgery, patients with L-FOG, as a group, were more impaired in executive functioning than control patients. However, individual data analysis showed preserved executive functions in 11 patients with L-FOG. In addition, there was no correlation between L-FOG severity and the degree of executive impairment. Therefore, frontal dysfunction may be one mechanism underlying L-FOG in a number of patients with Parkinson's disease. However, since some patients develop L-FOG despite the preservation of executive functions, lesions or dysfunction of other neuronal structures are likely to be involved.

Subthalamic nucleus versus pedunculopontine nucleus stimulation in Parkinson disease: synergy or antagonism?

Stimulation of the subthalamic nucleus (STN) improves the cardinal features of Parkinson disease (PD). However, its efficacy on gait disorders is less satisfying in the long term. In recent years, the pedunculopontine (PPN) nucleus has emerged as a possible promising deep brain stimulation target for gait disorders in PD. In this review, we examine whether STN and PPN act synergistically or antagonistically. Results suggest that the combination of STN and PPN stimulations leads to a significant further improvement in gait as compared with STN stimulation alone, but additive effects on the classical motor triad are questionable. Thus, they highlight the specificity of STN stimulation over PPN's for the PD cardinal features and the specificity of PPN stimulation over STN for gait disorders. In addition, low-frequency stimulation of the PPN may improve alertness. The additive rather than potentiating effects of STN and PPN stimulations suggest that they may be mediated by distinct pathways. Nevertheless, considering the inconsistencies in published results regarding the influence of PPN stimulation on gait disorders, work is still needed before one can know whether it will convert into a standard surgical treatment and to decipher its place beside STN stimulation.

Activation and inhibition of bimanual movements in school-aged children.

The development of motor activation and inhibition was compared in 6-to-12 year-olds. Children had to initiate or stop the externally paced movements of one hand, while maintaining that of the other hand. The time needed to perform the switching task (RT) and the spatio-temporal variables show different age-related evolutions depending on the coordination pattern (in- or anti-phase) and the type of transition (activation, selective inhibition, non selective inhibition) required. In the anti-phase mode, activation perturbs the younger subjects' responses while temporal and spatial stabilities transiently decrease around 9 years when activating in the in-phase mode. Aged-related changes differed between inhibition and activation in the anti-phase mode, suggesting either the involvement of distinct neural networks or the existence of a single network that is reorganized. In contrast, stopping or adding one hand in the in-phase mode shows similar aged-related improvement. We suggest that selectively stopping or activating one arm during symmetrical coordination rely on the two faces of a common processing in which activation could be the release of inhibition.

Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease.

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.

[Deep brain stimulation and gait disorders in Parkinson disease]. / Stimulation cérébrale profonde et troubles de la marche dans la maladie de Parkinson.

INTRODUCTION: Gait disorders and freezing of gait (FOG) are seen in most patients with advanced Parkinson disease. Response to levodopa and deep brain stimulation is variable across patients. STATE OF ART: Thalamic stimulation is ineffective on gait and can even worsen balance when bilaterally applied. Pallidal stimulation moderately improves gait disorders and FOG although this effect tends to wane after three to five years. Stimulation of the subthalamic nucleus (STN) improves levodopa-responsive gait disorders and FOG. However, some patients worsen after STN stimulation and others are better improved under levodopa than under STN stimulation. Synergistic effects of the two treatments have been reported. As for pallidal stimulation, there is a failure of long-term STN stimulation to improve gait, probably due to the involvement of non-dopaminergic pathways as the disease progresses. Levodopa-resistant gait disorders and FOG do not usually benefit from STN stimulation. In the rare cases of levodopa-induced FOG, STN stimulation may be indirectly effective, as it enables reduction or arrest of the levodopa treatment. PERSPECTIVES: Pedunculopontine nucleus stimulation has recently been performed in small groups of patients with disabling gait disorders and FOG. Although encouraging, the first results need to be confirmed by controlled studies involving larger series of patients. CONCLUSIONS: Overall, gait disorders remain a motor PD symptom that is little improved, or only temporarily, by current pharmacological and surgical treatments. Patient management is complex.

Pedunculopontine nucleus stimulation induces monocular oscillopsia.

Two patients with Parkinson's disease with pedunculopontine nucleus (PPN) stimulation for gait impairments reported "trembling vision" during the setting of the electrical parameters, although there was no clinically observable abnormal eye movement. Oculomotor recordings revealed frequency locked voltage dependent vertical or oblique movements of the eye ipsilateral to the active contact, suggesting current spreading to the mesencephalic oculomotor fibres. These results emphasise the difficulty of stimulating this mesencephalic region.

Gait is associated with an increase in tonic firing of the sub-cuneiform nucleus neurons.

In animals, the pedunculopontine (PPN) and the sub-cuneiform (SCU) nuclei located in the upper brainstem are involved during the processing of gait. Similar functional nuclei are suspected in humans but their role in gait is unclear. Here we show that, using extra-cellular recordings of the PPN/SCU region obtained in two parkinsonian patients, the SCU neurons increased their firing rate without modifying their firing pattern during mimicked steps. We conclude that SCU neurons are activated during gait processes.

Effects of subthalamic nucleus stimulation and levodopa on freezing of gait in Parkinson disease.

OBJECTIVE: We studied the effects of subthalamic nucleus (STN) stimulation vs levodopa on freezing of gait (FOG) and gait impairments in a large consecutive series of patients with Parkinson disease with bilateral STN stimulation. METHODS: One hundred twenty-three patients performed the Stand Walk Sit Test before and 1 year after surgery both off and on levodopa and off and on stimulation. RESULTS: Before surgery, 25 patients displayed FOG episodes and 48 were unable to complete the Stand Walk Sit Test when off levodopa. Both symptoms were alleviated by levodopa. After surgery, STN stimulation reproduced the improvement induced by levodopa before surgery in all but two patients with FOG and five others unable to walk. In 11 patients, FOG or inability to perform the test first occurred after surgery. In all patients but those experiencing FOG during the Stand Walk Sit Test before surgery, the benefit of STN stimulation did not reach that of levodopa before surgery. In patients with FOG before surgery, the effect of STN stimulation did not differ from that of levodopa either before or after surgery. CONCLUSIONS: Overall, subthalamic nucleus stimulation improved levodopa-responsive freezing of gait in most patients, although it was not always as effective as levodopa to improve gait impairments. In addition, surgery can induce gait problems in some patients.

3D analysis of posturo-kinetic coordination associated with a climbing task in children and teenagers.

The aim of this study was to characterize the modifications of the posturo-kinetic coordination during a climbing task as a function of postural and/or movement constraints in children (8-10 years) and adolescents (10-15 years). A 3D-analysis of forces was recorded for different movement amplitudes and types of holds. The results show the involvement of horizontal and vertical forces to maintain equilibrium during the steady state changes for different experimental groups. The contribution of horizontal and vertical forces changes in the course of movement realization. The vertical momentum (Iz) is mainly involved in the movement initiation: this role is mostly meaning for children. The horizontal momentum (Ih) is mainly involved in controlling equilibrium: this role is mostly meaning for adolescents.

Hand and gender differences in the organization of aiming in 5-year-old children.

The aim of the present study was to analyze the organization of aiming movements in right-handed children aged 5 years, depending on gender and hand used to perform the task. We first tested the hypothesis that aiming movements are predominantly organized in a feed-forward manner before the age of six. Using a direction pre-cueing protocol, we analyzed the effect of gender and hand used to perform the task on reaction time (RT), movement time (MT), spatial accuracy (SA) and acceleration profiles (APs) in children aged 5 years. Differences in RT between the uncued and pre-cued conditions suggest that the direction is actually specified prior to the execution of the movement at the age of five. However, the results also show significant hand and gender effects on MTs, spatial error and APs. Specifically, in girls, MT and kinematics profiles vary as a function of hand and target localization, whereas this is not the case in boys. In addition, SA is lower when aiming with the non-dominant hand in boys, but not in girls. These results suggest that multiple movement strategies are already available to the child at the age of five. Girls appear to be able to change movement strategy as a function of the constraints of the task, resulting in a stability of spatial accuracy (SA). On the contrary, the functional advantage of the right hand on MT and SA generally reported in right-handed males is not present in the boys at the age of five.

Influence of the movement parameter to be controlled on manual RT asymmetries in right-handers.

In this experiment we test whether the effects of manual asymmetries on movement preparation depend on the parameter (amplitude or direction) to be programmed. In two experiments, only the amplitude, or the direction, of aiming movements was constrained. Reaction and movement times were measured. Results show that RTs are always shorter for left-hand than for right-hand movements. There is an effect of target extent in the amplitude condition, but not in the direction one. RTs for ipsilateral movements are shorter than RTs for contralateral movements. These results are discussed in the light of the processes involved in setting the amplitude or direction of the movement and with regard to the competency of the two hemispheres regarding these processes.

Effects of the type of holds and movement amplitude on postural control associated with a climbing task.

The aim of the present work was to characterize the modifications of the postural adjustments during a climbing task as a function of postural and/or movement constraints. The variations of the horizontal and vertical forces and momentum were analyzed for different movement amplitudes and types of holds. The results show that the horizontal momentum is influenced by all experimental conditions before the onset of movement. By contrast, the vertical momentum is only influenced by the amplitude of the movement, after its onset. These results confirm the hypothesis of a dual function of the anticipatory postural adjustments. The horizontal momentum is mainly involved in the control of equilibrium. The vertical momentum contributes to the movement initiation.

Contribution of ankle, knee, and hip joints to the perception threshold for support surface rotation.

The purpose of the present experiment was to investigate the extent to which subjects can perceive, at very slow velocities, an angular rotation of the support surface about the medio-lateral axis of the ankle, knee, hip, or neck joint when visual cues are not available. Subjects were passively displaced on a slowly rotating platform at .01, .03, and .05 deg/sec. The subjects' task was to detect movements of the platform in four different postural conditions allowing body oscillations about the ankle, knee, hip, or neck joint. In Experiment 1, subjects had to detect backward and forward rotation (pitching). In Experiment 2, they had to detect left and right rotations of the platform (rolling). In Experiment 3, subjects had to detect both backward/forward and left/right rotations of the platform, with the body fixed and the head either fixed or free to move. Overall, when the body was free to oscillate about the ankle, knee, or hip joints, a similar threshold for movement perception was observed. This threshold was lower for rolling than for pitching. Interestingly, in these postural conditions, an unconscious compensation in the direction opposite to the platform rotation was observed on most trials. The threshold for movement perception was much higher when the head was the only segment free to oscillate about the neck joint. These results suggest that, in static conditions, the otoliths are poor detectors of the direction of gravity forces. They also suggest that accurate perception of body orientation is improved when proprioceptive information can be dynamically integrated.

[Three-dimensional analysis of variations of the forces associated with the climbing task in adolescents]. / Analyse tridimensionnelle des variations de forces associées à une tâche d'escalade chez des adolescents.

The efficient performance of voluntary movements requires a precise coordination between posture and movement. Anticipatory postural adjustments are believed to minimize the perturbation of balance triggered by the movement. This is particularly important in rock climbing where the unstable posture requires a fine balance control to preserve equilibrium. The aim of this study was to determine the spatial and temporal characteristics of the postural adjustments and movement in a climbing task for ten right-handed beginner children (5 boys and 5 girls) aged 10 to 15 years. A climbing ergometer was used for the experiment. The apparatus consists of four plates on which artificial climbing holds are secured. Using three-dimensional strain gauges we analyzed the three components of the forces applied at each hold. The signals were sampled at 100 Hz amplified and recorded on a personal computer. The climbing frame was adjusted to the anthropometry of each child. The task was to move one foot from one hold to another, and to actually climb onto the latter. Three levels of difficulty, corresponding to 1/3, 2/3, and 3/3 of shank length were tested. Subjects performed 5 trials with each foot at each level. The effect of three variables were analyzed: gender, laterality (right or left moving foot) and task difficulty. The force distribution was analyzed over a 400 ms period of steady state before the onset of movement. For all subjects and for all conditions, a greater force was applied to the right foot for the vertical forces and on the left foot for the lateral forces. In other words the subjects were standing over their right foot instead of exactly spreading their weight between the two legs. The onset of movement was always preceeded by a reproducible sequence of anticipatory postural adjustments involving the three supporting segments. This sequence was the same for the three components and started with the controlateral hand followed by the homolateral hand and then the controlateral foot. On the hand holds, the anticipation increased with the difficulty of the task, whereas movement time remained constant across all experimental conditions. The effect of task difficulty on the latencies of the anticipatory postural adjustments was more pronounced for the female subjects. The analysis of the load variations occurring during the movement along the three axes showed that the weight was transferred mainly to the controlateral foot but also to the hands. However the homolateral hand was never very involved. On the vertical component, there was a main effect of laterality. For a left foot movement, the force variation on the right controlateral side was more important than for a right foot deplacement. In addition there was a main effect of gender showing that the boys "pulled" more on their hands than the girls. This effect was stronger for a right foot movement. Compared with adults and age-matched boys, the girls seemed to use a more lateral, an expert-like, strategy.

Effects of a protein synthesis inhibitor on the hormonally mediated regression and death of motoneurons in the tobacco hornworm, Manduca sexta.

The larval-pupal transformation of Manduca sexta is accompanied by the loss of the abdominal prolegs. The proleg muscles degenerate, the dendritic arbors of proleg motoneurons regress, and a subset of the proleg motoneurons dies. The regression and death of proleg motoneurons are triggered by the prepupal peak of ecdysteroids in the hemolymph. To investigate the possible involvement of protein synthesis in these events, we gave insects repeated injections of the protein synthesis inhibitor, cycloheximide (CHX), during the prepupal peak. Examination of insects 3-5 days following CHX treatment showed that CHX inhibited the death of proleg motoneurons and the production of pupal cuticle in a dose-dependent fashion. When insects were allowed to survive for 10 days after the final CHX injection, motoneuron death and pupal cuticle production sometimes occurred belatedly, apparently in response to the ecdysteroid rise that normally triggers adult development. CHX treatments that inhibited motoneuron death were less effective in inhibiting dendritic regression in the same neurons. In another set of experiments, abdomens were isolated from the ecdysteroid-secreting glands prior to the prepupal peak, and infused with 20-hydroxyecdysone (20-HE). Single injections of CHX delivered just prior to the start of the 20-HE infusion inhibited motoneuron death and pupal cuticle production, but in the range of doses tested, did not prevent dendritic regression. Our findings suggest that protein synthesis is a required step in the steroid-mediated death of proleg motoneurons, and that dendritic regression is less susceptible to inhibition by CHX than is motoneuron death.

The growth cones of identified motoneurons in embryonic zebrafish select appropriate pathways in the absence of specific cellular interactions.

Developing motoneurons in zebrafish embryos follow a stereotyped sequence of axonal outgrowth and accurately project their axons to cell-specific target muscles. During axonal pathfinding, an identified motoneuron pioneers the peripheral motor pathway. Growth cones of later motoneurons interact with the pioneer via contact, coupling, and axonal fasciculation. In spite of these interactions, ablation of the pioneer motoneuron does not affect the ability of other identified motoneurons to select the pathways that lead to appropriate target muscles. We conclude that interactions between these cells during pathfinding are not required for accurate pathway selection.

Effects of gymnastics training on postural responses to stance perturbations.

The aim of the present experiment was twofold: (a) document the developmental course of postural responses to stance perturbations causing backward body sway and (b) investigate the plasticity of these responses by assessing the changes occurring in their organization as a result of gymnastics training. Fourteen untrained children (7 to 10 and 11 to 16 years old) and 15 age-matched gymnasts were tested on a movable platform. Four conditions were used: two-legged vs. one-legged stance x vision absent vs. present. Effects of age and training were assessed on the response latencies of eight muscles. Results showed no significant effect of age, but both stance and visual conditions affected the untrained subjects' response latencies. Wee found a significant effect of training on the response latency for the upper body muscles located on the frontal aspect of the body. This effect reflects an increase in gymnasts' response latencies as compared with controls'. Stance, but not vision, affected the responses of the trained subjects. Some implications of these results are discussed.

Postural adjustments to head movements in the cat.

Head movements induced by motor cortex stimulation in the cat are accompanied by variations in the vertical force exerted by each limb. These postural responses were found to show stereotyped patterns: with head dorsiflexions an increase was observed in the force exerted by the anterior limbs and a decrease at the posterior limb level. From comparison between the latencies of the force variations, the beginning of head acceleration, and EMG activity in the limb extensor muscles, it was concluded that triggering of these postural responses is not reflex, but depends on the same command as the movement itself. This early response might be a means of avoiding the downward movement of the trunk which would otherwise result from the reaction force corresponding to the upward head movement.

Postural responses to changing task conditions.

The experimental goal was to investigate discrepancies in the literature concerning postural adaptation and to determine if the prior presentation of horizontal perturbations affected the amplitude of responses to rotational perturbations. Surface EMG recordings from lower leg muscles (gastrocnemius (GAS) and tibialis anterior (TA)) were recorded in twelve subjects, and the amplitudes of the responses were statistically analyzed. We did not find differences between the responses to rotational perturbations which preceded or followed horizontal perturbations. This finding did not support the hypothesis that differences in the order of presentation of the different types of perturbations accounted for the discrepancies in the literature. Furthermore, our design did not show the progressive elimination of the GAS response within three to five sequential trials. Instead, we found a slow but significant response amplitude reduction over ten trials without yielding a permanent disappearance of the response. When analyzing the GAS responses to the rotational perturbations only, we found two components that contributed to the response reduction: 1) an initial reduction between trials one and subsequent trials, which could be due to habituation of a startle-like response; and 2) a second reduction which was more gradual. Our results also showed an immediate change in the response amplitude on the first trial, when the type of perturbation was changed. This is inconsistent with the view that ankle musculature stretch and joint movement are the primary inputs driving the postural responses. Since small ankle dorsiflexing rotations produced by the platform translations caused large GAS responses while large ankle dorsiflexing rotations produced by direct platform rotations caused small GAS responses, this suggests that multiple sensory inputs contribute to the responses. We propose that an initial compensation to a new perturbation type occurs within the first trial by the integration of these divergent sensory inputs.