Control of voluntary and reflexive saccades in Parkinson’s disease

Eight patients with idiopathic Parkinson’s disease (PD) were compared with a group of age-matched controls on both reflexive saccade and antisaccade tasks. While reflexive, visually guided saccades led to equivalent performance in both groups, PD patients were slower, made more errors, and showed reduced gain on antisaccades (AS). This is consistent with previous results showing that PD patients have no difficulty with reflexive saccades but show deficiencies in a number of voluntary saccade paradigms. Moreover, visual information in the form of landmarks improves AS performance more for PD patients than controls, a finding analogous to results seen with other motor acts such as target-directed pointing. Results are discussed in terms of a two-process model of attention and eye movements. Received: 13 October 1998 / Accepted: 11 May 1999     

Interval timing and Parkinson’s disease: heterogeneity in temporal performance

Interval timing deficiencies in Parkinson’s disease (PD) patients have been a matter of debate. Here we test the possibility of PD heterogeneity as a source for this discrepancy. Temporal performance of PD patients and control subjects was assessed during two interval tapping tasks and during a categorization task of time intervals. These tasks involved temporal processing of intervals in the hundreds of milliseconds range; however, they also covered a wide range of behavioral contexts, differing in their perceptual, decision-making, memory, and execution requirements. The results showed the following significant findings. First, there were two clearly segregated subgroups of PD patients: one with high temporal variability in the three timing tasks, and another with a temporal variability that did not differ substantially from control subjects. In contrast, PD patients with high and low temporal variability showed similar perceptual, decision-making, memory, and execution performance in a set of control tasks. Second, a slope analysis, designed to dissociate time-dependent from time-independent sources of variation, revealed that the increase in variability in this group of PD patients was mainly due to an increment in the variability associated with the timing mechanism. Third, while the control subjects showed significant correlations in performance variability across tasks, PD patients, and particularly those with high temporal variability, did not show such task correlations. Finally, the results showed that dopaminergic treatment restored the correlation effect in PD patients, producing a highly significant correlation between the inter-task variability. Altogether, these results indicate that a subpopulation of PD patients shows a strong disruption in temporal processing in the hundreds of milliseconds range. These findings are discussed in terms of the role of dopamine as a tuning element for the synchronization of temporal processing across different behavioral contexts in PD patients.     

Force coordination during bimanual task performance in Parkinson’s disease

We investigated within- and between-hand grip-load force coordination in medically managed Parkinson’s disease (PD) patients during bimanual tasks involving realistic actions. Increased grip force production and evidence of bradykinesia were expected in PD patients. Force coordination indices were also expected to be reduced in PD, due to impaired anticipatory force control. Increased grip force, bradykinesia, and abnormal load force production were exhibited in PD patients as compared to healthy controls. Indices of between-hand load force coordination, but not between-hand grip force coordination, were reduced in PD patients. Discrepancies in the strength of within-hand force coordination with respect to hand action were also noted in PD patients. Increased grip force production, in conjunction with abnormal load force production, may result in reduced fine motor control in PD patients during daily activities. Integrating quantitative analyses of realistic motor function in clinic may assist clinicians in evaluating the effectiveness of medical intervention in PD patients.     

Parkinson’s disease and Alzheimer’s disease: a Mendelian randomization study

Background

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the top two common neurodegenerative diseases in elderly. Recent studies found the α-synuclein have a key role in AD. Although many clinical and pathological features between AD and PD are shared, the genetic association between them remains unclear, especially whether α-synuclein in PD genetically alters AD risk.

Results

We did not obtain any significant result (OR?=?0.918, 95% CI: 0.782–1.076, P?=?0.291) in MR analysis between PD and AD risk. In MR between α-synuclein in PD with AD risk, we only extracted rs356182 as the IV through a strict screening process. The result indicated a significant association based on IVW method (OR?=?0.638, 95% CI: 0.485–0.838, P?=?1.20E-03). In order to examine the robustness of the IVW method, we used other three complementary analytical methods and also obtained consistent results.

Conclusion

The overall PD genetic risk factors did not predict AD risk, but the α-synuclein susceptibility genetic variants in PD reduce the AD risk. We believe that our findings may help to understand the association between them, which may be useful for future genetic studies for both diseases.

     

Attention and reach-to-grasp movements in Parkinson’s disease

The role of attention in grasping movements directed at common objects has not been examined in Parkinson’s disease (PD), though these movements are critical to activities of daily living. Our primary objective was to determine whether patients with PD demonstrate automaticity in grasping movements directed toward common objects. Automaticity is assumed when tasks can be performed with little or no interference from concurrent tasks. Grasping performance in three patient groups (newly diagnosed, moderate, and advanced/surgically treated PD) on and off of their medication or deep brain stimulation was compared to performance in an age-matched control group. Automaticity was demonstrated by the absence of a decrement in grasping performance when attention was consumed by a concurrent spatial-visualization task. Only the control group and newly diagnosed PD group demonstrated automaticity in their grasping movements. The moderate and advanced PD groups did not demonstrate automaticity. Furthermore, the well-known effects of pharmacotherapy and surgical intervention on movement speed and muscle activation patterns did not appear to reduce the impact of attention-demanding tasks on grasping movements in those with moderate to advanced PD. By the moderate stage of PD, grasping is an attention-demanding process; this change is not ameliorated by dopaminergic or surgical treatments. These findings have important implications for activities of daily living, as devoting attention to the simplest of daily tasks would interfere with complex activities and potentially exacerbate fatigue.     

Submovements during pointing movements in Parkinson’s disease

Velocity irregularities frequently observed during deceleration of arm movements have usually been interpreted as corrective submovements that improve motion accuracy. This hypothesis is re-examined here in application to movements of Parkinson’s disease (PD) patients in which submovements are specifically frequent. Pointing movements in patients and age-matched controls to large and small targets in three movement modes were studied. The modes were discrete (stop on the target), continuous (reverse on the target), and passing (stop after crossing the target). Two types of submovements were distinguished, gross and fine. In both groups, gross submovements were more frequent during the discrete and passing than continuous mode, specifically for large targets. This suggested that gross submovements were fluctuations accompanying motion termination (stabilization at the target) that was included in discrete and passing but not continuous movements. Gross submovements were specifically frequent in patients, suggesting that PD causes deficiency in smooth motion termination. Although in both groups fine submovements were more frequent for small than large targets, this relation was also observed in passing movements after crossing the target, i.e., when no corrections were needed. This result, together with higher jerk of the entire trajectory found for smaller targets, indicates that fine submovements may also be not corrective adjustments but rather velocity fluctuations emerging due to low speed of movements to small targets. This interpretation is consistent with the recognized inability of PD patients to promptly change generated force as well as to quickly re-plan current motion. The results suggest a need to re-examine the traditional interpretation of submovements in PD and the related theory that the production of iterative submovements is a strategy used by patients to compensate for a decreased initial force pulse.     

Can the disease course in Parkinson’s disease be slowed?

Background

The diagnosis of Parkinson’s disease (PD), which is needed for useful symptomatic therapy, is based on clinical criteria. However, it became quite clear in recent years that the same features can occur through different etiopathogenic mechanisms. Even a pathological diagnosis of PD, based on the demonstration of α-synuclein deposits in a typical distribution, can result from different causes and, vice versa, nigral cell loss can occur without α-synuclein deposition.

Discussion

Thus far, attempts to influence the progression of PD have failed. However, since the clinical manifestations of PD can be the result of diverse mechanisms, a single intervention may not be able to slow the course of the disease in all patients. Indeed, targeting the underlying pathogenic processes, which differ among cases, may be more effective. PD may develop as a consequence of mitochondrial damage, which itself may result from a variety of genetic or environmental factors. Correction of the ensuing oxidative stress may theoretically be useful in these PD patients, but will not affect the progression of the disease among other PD patients in whom an identical clinical syndrome derives from defects in other pathways such as the ubiquitin-proteasome system and lysosomal dysfunction, among others.

Summary

Precision medicine can now be used to identify the underlying pathogenic mechanisms in individual patients, paving the way to the development of real disease modification through a pathway-oriented approach, aimed at the underlying biologic processes of disease occurrence and evolution.

     

Locomotor response to levodopa in fluctuating Parkinson’s disease

The aim of this study was to quantify the dynamic response of locomotion to the first oral levodopa administration of the day in patients with fluctuating Parkinson’s disease (PD). Stride length, walking speed, cadence and gait variability were measured with an ambulatory gait monitor in 13 PD patients (8 males) with a clinical history of motor fluctuations. The Unified Parkinson’s Disease Rating Scale (UPDRS) gait score (part 29) was also determined by a movement disorders specialist from video recordings. Subjects arrived in the morning in an ‘off’ state (no PD medication) and walked for a maximum length of 100 m. They then took their usual morning dose of oral levodopa and repeated the walking task at 13 min intervals (on average) over a 90 min period. Changes in stride length over time were fit with a Hill (Emax) function. Latency (time until stride length increased 15% of the difference between baseline and maximum response) and the Hill coefficient (shape of the ‘off–on’ transition) were determined from the fitted curve. Latency varied from 4.7 to 53.3 min post-administration [23.31 min (SD 14.9)], and was inversely correlated with age at onset of PD (R = −0.83; P = 0.0004). The Hill coefficient (H) ranged from a smooth hyperbolic curve (0.9) to an abrupt ‘off–on’ transition (16.9), with a mean of 8.1 (SD 4.9). H correlated with disease duration (R = 0.67; P = 0.01) and latency (R = 0.67; P = 0.01), and increased with Hoehn & Yahr stage in the ‘off’ state (P = 0.02) from 5.7 (SD 3.5) (H&Y III) to 11.9 (SD 4.7) (H&Y IV). Walking speed correlated with changes in mean stride length, whereas cadence and gait variability did not. UPDRS gait score also reflected improving gait in the majority of subjects (8), providing clinical confirmation of the objective measures of the locomotor response to levodopa. Increasing abruptness (H) of the ‘off–on’ transition with disease duration is consistent with results from finger-tapping studies, and may reflect reduced buffering capacity of pre-synaptic nigrostriatal dopaminergic neurons. Ambulatory monitoring of gait objectively measures the dynamic locomotor response to levodopa, and this information could be used to improve daily management of motor fluctuations. Dr. Steven Moore was supported in part by NASA grant NNJ04HF51G.     

The control of an action in Parkinson’s disease

We studied, in Parkinson’s disease (PD) patients and healthy control subjects, the kinematics of the action formed by two successive motor acts: reaching-grasping an object (first target) and placing it on a second target. We examined the effects of extrinsic (i.e., distance) and intrinsic (i.e., size) properties of the second target on the various kinematic phases of reaching-grasping. We randomly varied distance and size of both stimuli across the experimental session. The kinematics of the reach initial phase of both patients and controls was influenced by the distance of both the first and the second target. In particular, peak acceleration increased for farther position of the second target. However, in the subsequent phase, patients, differently from controls, modified their reaching kinematics, removing the effects of second target position. These results were due neither to a visual interference effect of the second target on reaching-grasping nor to the complexity of movement sequence. Finally, the size of the second target did not affect grasp kinematics of both patients and controls. The results of the present study support the hypothesis that PD patients are able to compute the general program of an action in which extrinsic properties of both the actual and the final target are computed. However, PD patients re-program movement during its execution. This suggests a decay of the motor program. That is, basal ganglia can be involved in storing the plan of an action and in controlling its correct execution. Received: 16 November 1998 / Accepted: 30 June 1999     

Pedunculopontine nucleus deep brain stimulation in Parkinson’s disease

Postural instability and gait difficulty (PIGD) are commonly observed in advanced Parkinson’s disease. The neuronal mechanism of PIGD is not fully understood. Dysfunction of the pedunculopontine nucleus (PPN) might be a possible cause of these symptoms. The autopsy studies of subjects with PIGD revealed a neurodegenerative process involving mainly PPN cholinergic neurons. The PPN participates in the locomotion processes by initiation, modulation and execution of stereotyped patterns of movement. The standard neurosurgical treatment of PD is subthalamic deep brain stimulation (STN DBS). Clinical results revealed low efficiency of STN DBS on PIGD. Preliminary results of simultaneous PPN and STN DBS are very promising. Only a few reports have been published until now; a significant improvement of PIGD was observed in both ON and OFF L-dopa states.     

Perceptual factors contribute to akinesia in Parkinson’s disease

Parkinson’s disease (PD) patients have longer reaction time (RT) than age-matched control subjects. During the last decades, conflicting results have been reported regarding the source of this deficit. Here, we addressed the possibility that experimental inconsistencies originated in the composite nature of RT responses. To investigate this idea, we examined the effect of PD on different processes that compose RT responses. Three variables were manipulated: the signal quality, the stimulus–response compatibility and the foreperiod duration. These variables have been shown to affect, respectively, the ability to extract the relevant features of the stimulus (perceptual stage), the intentional selection of the motor response (cognitive stage) and the implementation of the muscle command (motor stage). Sixteen PD patients were tested on and off-medication and compared with an age and gender-matched control group. Results indicated that degrading the legibility of the response stimulus affected the latency of simple key-press movements more dramatically in the off-medication PD group than in the control population. The stimulus–response compatibility and the foreperiod duration had similar effects in the two groups. Interestingly, the response slowing associated with the degradation of the stimulus was the same whether the patients were on or off dopaminergic medication. This suggests that the high-level perceptual deficits observed in the present study do not have a dopaminergic origin. This work was supported by the French Ministry of Education, Research and Technology.     

Coordination of grasping and walking in Parkinson’s disease

Studies on grasp control underlying manual dexterity in people with Parkinson disease (PD) suggest that anticipatory grasp control is mainly unaffected during discrete tasks using simple two-digit grasp. Nevertheless, impaired hand function during daily activities is one of the most disabling symptoms of PD. As many daily grasping activities occur during functional movements involving the whole body, impairments in anticipatory grasp control might emerge during a continuous dynamic task such as object transport during walking. In this case, grasp control must be coordinated along with multiple body segments. The present study investigated the effect of PD on anticipatory grasp control and intersegmental coordination during walking with a hand-held object. Nine individuals with idiopathic PD (tested OFF and ON medication) and nine healthy age-matched controls carried a grip instrument between their right thumb and index finger during self-paced and fast walking. Although the amplitude of grip forces was higher in standing and walking for subjects with PD, both subjects with PD and control subjects coupled grip and inertial force changes in an anticipatory fashion while walking. However, gait-induced motions of the object relative to that of the trunk (i.e., dampening) was reduced in subjects with PD. Medication increased the dampening in all subjects with PD. We suggest that these differences are associated with impairments in intersegmental coordination.     

Microglial cells and Parkinson’s disease

Chronic inflammation mediated by microglial cells is the fundamental process contributing to the death of dopamine (DA)-producing neurons in the brain. Production of inflammatory products by these microglial cells characterizes the slow destructive process in Parkinson’s disease (PD). The activation of microglial cells and the generation of pro-inflammatory cytokines that characterize PD are mediated by several different signaling pathways, with the activation of the respiratory burst by microglial cells being a critical event in the ultimate toxicity of DA-neurons. The work on our lab is concerned with understanding the mechanisms of activation, response, and therapeutic targets of microglial cells, with the aim to provide more effective treatments for PD and other inflammatory diseases of the CNS.     

Deficits in task-set maintenance and execution networks in Parkinson’s disease

Patients with Parkinson’s disease have difficulties with self-initiating a task and maintaining a steady task performance. We hypothesized that these difficulties relate to reorganization in the sensorimotor execution, cingulo-opercular task-set maintenance, and frontoparietal adaptive control networks. We tested this hypothesis using graph theory-based network analysis of a composite network including a total of 86 nodes, derived from the three networks of interest. Resting-state functional magnetic resonance images were collected from 30 patients with Parkinson’s disease (age 42–75 years, 11 females; Hoehn and Yahr score 2–3, average 2.4 ± 0.4) in their off-medication state and 30 matched control subjects (age 44–75 years, 10 females). For each node, we calculated strength as a general measure of connectivity, global efficiency and betweenness centrality as measures of functional integration, and clustering coefficient and local efficiency as measures of functional segregation. We found reduced node strength, clustering, and local efficiency in sensorimotor and posterior temporal nodes. There was also reduced node strength and betweenness centrality in the dorsal anterior insula and temporoparietal junction nodes of the cingulo-opercular network. These nodes are involved in integrating multimodal information, specifically related to self-awareness, sense of agency, and ultimately to intact perception of self-in-action. Moreover, we observed significant correlations between global disease severity and averaged graph metrics of the whole network. In addition to the well-known task-related frontostriatal mechanisms, we propose that the resting-state reorganization in the composite network can contribute to problems with self-initiation and task-set maintenance in Parkinson’s disease.     

Segment difficulty in two-stroke movements in patients with Parkinson’s disease

In the horizontal plane on a digitizer tablet, subjects made an elbow-extension, two-stroke movement away from the trunk to a first target and then on to a second target. If the two segments of the movement were executed in an integrative manner, the accuracy constraint on the first segment should have produced changes in kinematic features not only of that segment but also of the second segment. Two-stroke movements of ten Parkinson's disease (PD) patients and ten controls were studied to examine whether a high-accuracy constraint on the first segment influences the performance of the second, when the second target has either a high- or low-accuracy requirement. When the accuracy requirement of the second segment was low, both PD patients and controls showed that changing the first target size from large to small influenced the performance of not only the first segment but also the second segment. For the first segment, movement time, acceleration time, and deceleration time increased when moving to the small first target as compared to the large first target. The peak velocity and peak acceleration also decreased as the first target size decreased. For the second segment, similar patterns of kinematic changes in relation to the first segment were observed in all of these parameters. When the accuracy requirement of the second segment was high, the controls showed similar changes in the first and second segments in relation to the change of first target sizes. In contrast, the PD patients showed that the target size that defined the first movement mainly influenced the performance of that segment. Among kinematic parameters tested for the second segment, only acceleration time increased as the first target size decreased. Other parameters in general did not change, regardless of whether movement of the first segment was made to the small or large target. These results indicate that the two-stroke movements of PD patients showed little evidence that they were planned and organized in an integrative manner when there was a high-accuracy constraint imposed on the second segment. On the other hand, control subjects performed two-stroke movements in a manner that suggested the two segments were planned and organized together regardless of an accuracy constraint imposed.     

Parkinson’s disease: a rethink of rodent models

Parkinson’s disease (PD) is a multifactorial disease with a complex etiology that results from genetic risk factors, environmental exposures and most likely a combination of both. Rodent models of parkinsonism aim to reproduce key pathogenic features of the syndrome including movement disorder induced by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the formation of α-synuclein containing Lewy body inclusions. Despite the creation of many excellent models, both chemically induced and genetically engineered, there is none that accurately demonstrates these features. Recent pathological staging studies in man have also emphasized the significant non-CNS component of PD that has yet to be tackled. Herein, we summarize rodent models of PD and what they offer to the field, and suggest future challenges and opportunities.     

Effects of pallidal deep brain stimulation and levodopa treatment on reaction-time performance in Parkinson’s disease

Basal ganglia-thalamocortical circuits play an important role in movement preparation and execution. Tracer, single-cell, and lesion studies in monkeys suggest the existence of topologically segregated motor and nonmotor basal ganglia cortical circuits. In this study we used deep brain stimulation (DBS) of the posteroventrolateral globus pallidus internus (GPi) in patients with Parkinson's disease to elucidate the function of the GPi in human sensorimotor behavior. This question was investigated by comparing the influence of DBS on patients' performance in various reaction-time tasks that differed with respect to cognitive but not motor requirements. As a main result, DBS improved performance on the different tasks independently of the complexity of the involved cognitive processing functions. Furthermore, the observed effects did not depend on the modality of the processed information. These results suggest that the functional state of the posteroventrolateral GPi selectively affects the motor stage in simple sensorimotor acts, because this stage was the only stage involved in all investigated tasks. In addition to DBS, we manipulated the levodopa medication state of the PD patients. In contrast to DBS, levodopa effects on reaction times were less consistent. Levodopa improved reaction times in choice reaction tasks significantly, while affecting reaction times in a simple reaction task to a lesser extent. Error analysis revealed that the medication-dependent reaction-time improvement in the choice reaction tasks was accompanied by an increase in errors, suggesting a shift of the speed-accuracy criteria of the patients. A similar pattern of results was not observed for the DBS effects. Taken together, our data are in agreement with recent findings in monkeys that indicate a topological organization of the GPi in which motor functions are localized in posterolateral regions apart from cognitive regions. Furthermore, our data show a way to uncover the subcortical-cortical circuitry serving human sensorimotor behavior.