Effects of five years of chronic STN stimulation on muscle strength and movement speed

This study examined the long-term effects of chronic subthalamic nucleus (STN) deep brain stimulation (DBS) using both clinical evaluation and laboratory motor control measures. Over a 5-year time period, changes in the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS) and movement speed and strength at the ankle joint were evaluated on and off STN DBS in eight patients with Parkinson’s disease (PD). Four patients were also studied at the elbow joint. Patients with PD originally received unilateral STN DBS between years 2001 and 2003. They were re-evaluated after 5 years of long-term STN DBS between years 2006–2008. At baseline (year 0) and after 5 years, patients with PD were tested off treatment and on STN DBS. In each testing condition, patients performed ballistic, single degree of freedom ankle dorsiflexion and ankle plantarflexion movements and peak velocity was calculated. Patients also performed maximal voluntary contractions at the ankle joint in both directions, and peak torque was calculated. Results showed increased motor UPDRS scores from year 0 to year 5, but STN DBS was efficacious in reducing them. In contrast to the increase in motor UPDRS scores, motor control results showed a marked improvement in peak velocity and peak torque over the 5-year time period in the off treatment condition, and STN DBS was efficacious by improving both peak velocity and peak torque. The current findings suggest that 5 years of chronic STN DBS can have beneficial effects on the motor system over the long term in discrete motor tasks in which maximal effort and maximal neural output is required.     

Does subthalamic nucleus stimulation affect the frontal limbic areas? A single-photon emission computed tomography study using a manual anatomical segmentation method

Among the basal ganglia nuclei, the subthalamic nucleus (STN) is considered to play a major role in output modulation. The STN represents a relay of the motor cortico-basal ganglia-thalamo-cortical circuit and has become the standard surgical target for treating Parkinson’s patients with long-term motor fluctuations and dyskinesia. But chronic bilateral stimulation of the STN produces cognitive effects. According to animal and clinical studies, the STN also appears to have direct or indirect connections with the frontal associative and limbic areas. This prospective study was conducted to analyse regional cerebral blood flow changes in single-photon emission computed tomography imaging of six Parkinson’s patients before and after STN stimulation. We particularly focused on the dorsolateral prefrontal cortex and the frontal limbic areas using a manual anatomical MRI segmentation method. We defined nine regions of interest, segmenting each MR slice to quantify the regional cerebral blood flow on pre- and postoperative SPECT images. We normalised the region-of-interest-based measurements to the entire brain volume. The patients showed increased activation during STN stimulation in the dorsolateral prefrontal cortex bilaterally and no change in the anterior cingulate and orbito-frontal cortices. In our study, STN stimulation induced activation of premotor and associative frontal areas. Further studies are needed to underline involvement of the STN with the so-called limbic system.     

Diagnosis of Parkinson's disease using electrovestibulography

In this paper, a new method for diagnosis of Parkinson’s disease (PD) based on the analysis of electrovestibulography (EVestG) signals is introduced. EVestG signals are in fact the vestibular response modulated by more cortical brain signals; they are recorded from the ear canal. EVestG data of 20 individuals with PD and 28 healthy controls were adopted from a previous study. The field potentials and their firing pattern in response to whole body tilt stimuli from both left and right ears were extracted. We investigated several statistical and fractal features of the field potentials and also their firing interval histograms followed by one-way analysis of variance to select pairs of features showing the most significant differences between individuals with Parkinson disease and the age-matched controls. Linear discriminant analysis classification was applied to every selected feature using a leave-one-out routine. The result of each feature’s classifier was used in a heuristic average voting system to diagnose PD patients. The results show more than 95% accuracy for PD diagnosis. Given that the patients were at different stage of disease, the high accuracy of the results is encouraging for continuing exploration of the EVestG application to PD diagnosis as it may provide a quick and non-invasive screening tool.     

Reduced Content of α-Synuclein in Peripheral Blood Leukocytes of Patients with <Emphasis Type="Italic">LRRK2</Emphasis>-Associated Parkinson’s Disease

Measurement of α-synuclein level in the peripheral blood was proposed as a diagnostic test for Parkinson’s disease. However, the results of these studies remain contradictory, probably because the examined samples included patients with different etiology of Parkinson’s disease. To verify this assumption we studied the levels of α-synuclein in peripheral blood leukocytes of patients with Parkinson’s disease associated with mutations in the gene of leucine-rich kinase 2 (LRRK2). The mean α-synuclein level was signifi cantly lower in patients with LRRK2-associated Parkinson’s disease (N=8) than in patients with sporadic form of the disease (N=33; p<0.02) and in controls (N=18; p<0.05). On the other hand, we found no differences in the level of α-synuclein level between patients with sporadic form of the disease and controls. We hypothesize that the level of α-synuclein in the peripheral blood largely depends on the etiology of the disease and cannot be used as a universal diagnostic test for Parkinson’s disease.     

Are automatic postural responses in patients with Parkinson’s disease abnormal due to their stooped posture?

 Abnormal automatic postural responses are thought to contribute to balance impairment in Parkinson’s disease. However, because postural responses are modifiable by stance, we have speculated that some postural abnormalities in patients with Parkinson’s disease are secondary to their stooped stance. We have studied this assumption by assessing automatic postural responses in 30 healthy subjects who were instructed either to stand upright or to assume a typical parkinsonian posture. During both conditions, subjects received 20 serial 4°’toe-up’ rotational perturbations from a supporting forceplate. We recorded short-latency (SL) and medium-latency (ML) responses from stretched gastrocnemius muscles and long-latency (LL) responses from shortened tibialis anterior muscles. We also assessed changes in the center of foot pressure (CFP) and the center of gravity (COG). The results were qualitatively compared to a previously described group of patients with Parkinson’s disease who, under these circumstances, typically have large ML responses, small LL responses and insufficient voluntary postural corrections, accompanied by a slow rate of backward CFP displacement and an increased posterior COG displacement. The stooped posture resulted in unloading of medial gastrocnemius muscles and loading of tibialis anterior muscles. Onset latencies of stretch responses in gastrocnemius muscles were delayed in stooped subjects, but the onset of LL responses was markedly reduced. Amplitudes of both ML and LL responses were reduced in stooped subjects. Prestimulus COG and, to a lesser extent, CFP were shifted forwards in stooped subjects. Posterior COG displacement and the rate of backward CFP displacement were diminished in stooped subjects. Voluntary postural corrections were unchanged while standing stooped. These results indicate that some postural abnormalities of patients with Parkinson’s disease (most notably the reduced LL responses) can be reproduced in healthy subjects mimicking a stooped parkinsonian posture. Other postural abnormalities (most notably the increased ML responses and insufficient voluntary responses) did not appear in stooped controls and may contribute to balance impairment in Parkinson’s disease. Received: 16 February 1998 / Accepted: 24 August 1998     

Startle responses in Parkinson patients during human gait

Falls frequently occur in patients with Parkinson’s disease (Bloem et al. 2001). One potential source for such falls during walking might be caused by the reaction to loud noises. In normal subjects startle reactions are well integrated in the locomotor activity (Nieuwenhuijzen et al. 2000), but whether this is also achieved in Parkinson patients is unknown. Therefore, in the present study, the startle response during walking was studied in eight patients with Parkinson’s disease and in eight healthy subjects. To examine how startle reactions are incorporated in an ongoing gait pattern of these patients, unexpected auditory stimuli were presented in six phases of the step cycle during walking on a treadmill. For both legs electromyographic activity was recorded from biceps femoris and tibialis anterior. In addition, we measured the stance and swing phases of both legs, along with the knee angles of both legs and the left ankle angle. In all subjects and all muscles, responses were detected. The pattern of the responses, latency, duration, and phase-dependent modulation was similar in both groups. However, the mean response amplitude was larger in patients due to a smaller habituation rate. No correlation was found between the degree of habituation and disease severity. Moreover, a decreased habituation was already observed in mildly affected patients, indicating that habituation of the startle response is a sensitive measure of Parkinson’s disease. The results complement the earlier findings of reduced habituation of blink responses in Parkinson’s disease. With respect to behavioral changes in healthy subjects we observed that startle stimuli induced a shortening of the step cycle and a decrease in range of motion. In the patient group, less shortening of the subsequent step cycle and no decrease in range of motion of the knee and ankle was seen. It is argued that the observed changes might contribute to the high incidence of falls in patients with Parkinson’s disease.Grants: This study was supported by an EU grant “Eurokinesis”.     

Evolution of postural stability after subthalamic nucleus stimulation in Parkinson’s disease: a combined clinical and posturometric study

Objectives: The occurrence of postural and balance disorders is a frequent feature in advanced forms of Parkinson’s disease (PD). However, the pathological substrate of these disturbances is poorly understood. Methods: In the present work, we investigated the evolution of posturometric parameters [center of pressure (CoP) displacement and CoP area] and axial scores between the pre-operative period and 3 months post-operative in seven PD patients who underwent bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). Results: After surgery, the patients leaned backwards much more regardless of the STN stimulation, suggesting that surgery could have a deleterious effect on postural adaptation. During the post-operative period, the improvement in axial and postural scores was similar under levodopatherapy and DBS. On the other hand, DBS of the STN significantly reduced the CoP displacement and the CoP area, whereas levodopatherapy tended only to reduce the CoP displacement and to increase the CoP area significantly. Conclusions: These data suggest that DBS of the STN and levodopa do not act on the same neurological systems involved in posture regulation. DBS of the STN could improve posture via a direct effect on the pedunculopontine nucleus, which is known to be involved in posture regulation.     

Neuronal discharge patterns in the Globus Pallidus pars interna in a patient with Parkinson’s disease and hemiballismus secondary to subthalamotomy

Alterations in the basal ganglia-thalamocortical “motor” circuit activity, have been proposed to explain many features associated with hypokinetic and hyperkinetic movement disorders. We describe the firing pattern of the globus pallidus pars interna in a Parkinson disease’s patient who developed Hemichorea-Ballismus subsequent to ipsilateral subthalamotomy, and compare findings to those from PD patients submitted to pallidotomy while in the OFF-medication state. Single units obtained from extracellular recordings were extracted and mean discharge frequency, interspike interval and coefficient of variation (defined as Tonicity Score) were computed. Discharge density histograms, analysis of distribution and spectral analysis were also performed. Mean firing frequency showed no significant difference between PD patients in the OFF state and the patient we report. However, a significant difference in tonicity was found for this patient characterized by a regular, non-bursting firing pattern. The findings indicate that in HB caused by lesions to STN in the parkinsonian state, GPi firing rates can be similar to and firing pattern more regular than those observed in GPi of PD patients OFF-medication with intact STN.     

Circadian distribution of motor-activity in unilaterally 6-hydroxy-dopamine lesioned rats

Sleep abnormalities in idiopathic Parkinson’s disease (PD) frequently consist in a reduction of total sleep time and efficacy and subsequent excessive daytime sleepiness. As it remains unclear whether these phenomena are part of the disease itself or result from pharmacological treatment, animal models for investigating the pathophysiology of sleep alterations in PD may add knowledge to this research area. In the present study, we investigate whether changes in circadian motor activity occur in 6-OHDA-lesioning model for PD, and allow a screening for disturbed sleep–waking behaviour. Activity measurements of six male Wistar rats with 6-OHDA-lesions in the medial forebrain bundle and six controls were carried out in two consecutive 12:12 h light–dark (LD) cycles. A computer-based video-analysis system, recording the animals’ movement tracks was used. Distance travelled and number of transitions between movement periods and resting periods were determined. Although 6-OHDA-lesioned animals show a reduced locomotor activity compared to non-lesioned rats, the circadian distribution basically remained intact. However, some lesioning effects were more pronounced in the resting phase than in the activity phase, possibly paralleling nocturnal akinesia in PD. In order to further elucidate the described phenomena, it will be necessary to perform studies combining sleep recordings with locomotor activity measurements.     

Chronic dopamine depletion augments the functional expression of K-ATP channels in the rat subthalamic nucleus

Symptoms of Parkinson's disease caused by dopamine depletion are associated with burst firing in the subthalamic nucleus (STN). Moreover, regularization or suppression of STN neuronal activity is thought to improve symptoms of Parkinson's disease. We reported recently that N-methyl-d-aspartate (NMDA) receptor stimulation of rat STN neurons evokes ATP-sensitive K⁺ (K-ATP) current via a Ca²⁺- and nitric oxide-dependent mechanism. The present studies were done to determine whether or not K-ATP channel function in STN neurons is altered in a model of chronic dopamine depletion. Brain slices were prepared from rats with unilateral dopamine depletion caused by intracerebral 6-hydroxydopamine (6-OHDA) injections. Whole-cell patch-clamp recordings showed that NMDA evoked more outward current at −70 mV and greater positive slope conductance in STN neurons located ipsilateral to 6-OHDA treatment compared to neurons located contralateral. Moreover, extracellular, loose-patch recordings showed that NMDA increased spontaneous firing rate in STN neurons in slices from normal rats, whereas NMDA produced a tolbutamide-sensitive inhibition of firing rate in STN neurons located ipsilateral to 6-OHDA treatment. These results show that K-ATP channel function in STN neurons is up-regulated by chronic dopamine deficiency. We suggest that K-ATP channel activation in the STN might benefit symptoms of Parkinson's disease.     

Impaired conflict monitoring in Parkinson’s disease patients during an oculomotor redirect task

Fallibility is inherent in human cognition and so a system that will monitor performance is indispensable. While behavioral evidence for such a system derives from the finding that subjects slow down after trials that are likely to produce errors, the neural and behavioral characterization that enables such control is incomplete. Here, we report a specific role for dopamine/basal ganglia in response conflict by accessing deficits in performance monitoring in patients with Parkinson’s disease. To characterize such a deficit, we used a modification of the oculomotor countermanding task to show that slowing down of responses that generate robust response conflict, and not post-error per se, is deficient in Parkinson’s disease patients. Poor performance adjustment could be either due to impaired ability to slow RT subsequent to conflicts or due to impaired response conflict recognition. If the latter hypothesis was true, then PD subjects should show evidence of impaired error detection/correction, which was found to be the case. These results make a strong case for impaired performance monitoring in Parkinson’s patients.     

Possible mechanisms of delay in initiation of voluntary movements

Studies were made of psychomotor responses and accompanying cortical evoked potentials in healthy subjects and patients with Parkinson’s disease. Measurements showed that delays in a variety of psychomotor responses resulted from delays in movement initiation. The frontal regions showed increases in the N2 component of evoked potentials and delayed development of P3 waves. It is suggested that delayed initiation of movements in patients with Parkinson’s disease might be associated with strengthening of frontal inhibitory systems, preventing the onset of movements. Laboratory for the Physiology of Higher Nervous Activity, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Makarov Bank, 199034 St. Petersburg, Russia. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 83, No. 1-2, pp. 109–116, January–February, 1997.     

A torque-based method demonstrates increased rigidity in Parkinson’s disease during low-frequency stimulation

Low-frequency oscillations in the basal ganglia are prominent in patients with Parkinson’s disease off medication. Correlative and more recent interventional studies potentially implicate these rhythms in the pathophysiology of Parkinson’s disease. However, effect sizes have generally been small and limited to bradykinesia. In this study, we investigate whether these effects extend to rigidity and are maintained in the on-medication state. We studied 24 sides in 12 patients on levodopa during bilateral stimulation of the STN at 5, 10, 20, 50, 130 Hz and in the off-stimulation state. Passive rigidity at the wrist was assessed clinically and with a torque-based mechanical device. Low-frequency stimulation at ≤20 Hz increased rigidity by 24 % overall (p = 0.035), whereas high-frequency stimulation (130 Hz) reduced rigidity by 18 % (p = 0.033). The effects of low-frequency stimulation (5, 10 and 20 Hz) were well correlated with each other for both flexion and extension (r = 0.725 ± SEM 0.016 and 0.568 ± 0.009, respectively). Clinical assessments were unable to show an effect of low-frequency stimulation but did show a significant effect at 130 Hz (p = 0.002). This study provides evidence consistent with a mechanistic link between oscillatory activity at low frequency and Parkinsonian rigidity and, in addition, validates a new method for rigidity quantification at the wrist.     

Pedunculopontine nucleus microelectrode recordings in movement disorder patients

The pedunculopontine nucleus (PPN) lies within the brainstem reticular formation and is involved in the motor control of gait and posture. Interest has focused recently on the PPN as a target for implantation of chronic deep brain stimulation (DBS) electrodes for Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) therapy. The aim of this study was to examine the neurophysiology of the human PPN region and to identify neurophysiological landmarks that may aid the proper placement of DBS electrodes in the nucleus for the treatment of PD and PSP. Neuronal firing and local field potentials were recorded simultaneously from two independently driven microelectrodes during stereotactic neurosurgery for implantation of a unilateral DBS electrode in the PPN in five PD patients and two PSP patients. Within the PPN region, the majority (57%) of the neurons fired randomly while about 21% of the neurons exhibited ‘bursty’ firing. In addition, 21% of the neurons had a long action potential duration and significantly lower firing rate suggesting they were cholinergic neurons. A change in firing rate produced by passive and/or active contralateral limb movement was observed in 38% of the neurons that were tested in the PPN region. Interestingly, oscillatory local field potential activity in the beta frequency range (∼25 Hz) was also observed in the PPN region. These electrophysiological characteristics of the PPN region provide further support for the proposed role of this region in motor control. It remains to be seen to what extent the physiological characteristics of the neurons and the stimulation-evoked effects will permit reliable identification of PPN and determination of the optimal target for DBS therapy.     

Neurosurgical interventions in the treatment of idiopathic Parkinson disease: neurostimulation and neural implantation

With the exception of thalamotomy for drug-refractory tremor, surgical therapy for Parkinson’s disease has been almost abondoned as treatment for Parkinsonian symptoms between 1965 and 1985. Reasons for this development relate to inconsistent postoperative results, complications associated with stereotactic surgical techniques and, most importantly, the advent of levodopa, which is still considered to be the gold standard in pharmacotherapy for Parkinson’s disease. However, both, the long-term experience with L-DOPA therapy on the one hand and the progress of advanced stereotactic techniques and fetal graft research on the other hand have lead to reconsideration of surgical therapy in Parkinson’s disease for patients, who can not be treated satisfactorily with medication. Both lesions (via thermocoagulation) and/or neurostimulation (via chronic intracerebral implantation of electrodes) in thalamic nuclei (nucleus ventralis oralis posterior/intermedialis thalami; VOP/VIM) may alleviate rest tremor in PD patients. In principle neurostimulation has the significant advantage of reversibility with regard to side effects in comparison to lesion surgery. Furthermore ventro-posterior pallidotomy or chronic stimulation in this structures may ameliorate bradykinesia and levodopa-induced dyskinesias. Additionally, ”switching-off” the subthalamic nucleus by neurostimulation has been reported to reduce rigidity, bradykinesia and levodopa-induced ON-OFF-fluctuations. On the other hand, neuronal transplantation of fetal nigral dopamine precursor cells aims at restoring the striatal dopamine deficit. Both animal and clinical experiments have shown that fetal grafts survive intrastriatal transplantation and may ensue moderate to satisfactory improvements, especially in regard to bradykinesia and ON-OFF-fluctuations. Further progress in the field of neuronal transplantation will largely depend on the development of alternative cell resources.     

Therapeutic Efficacy of the Neuroprotective Plant Adaptogen in Neurodegenerative Disease (Parkinson’s Disease as an Example)

Therapeutic efficacy of the plant neuroprotector Phytomix-40 in Parkinson’s disease was demonstrated. This preparation consists of the components from extracts of 40 plants, including some adaptogens (ginseng, eleutherococcus, Rhodiola rosea, etc.). The preparation normalized immune, antioxidant, and hormonal parameters in patients. The neuroprotective plant adaptogen can be used in complex therapy for Parkinson’s disease for improving its efficacy.     

P2X7 Receptor Signaling Pathway as a Therapeutic Target for Neurodegenerative Diseases

A recent study suggested that neuroinflammation plays a major role in the pathogenesis of a number of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Although the precise mechanism is obscure, dysregulation of the signaling transduction pathway in microglia may enhance inflammation, leading to synaptic dysfunction and ultimately to neuronal cell death. The expression and function of the P2X7 receptor (P2X7R), an ATP-gated ion channel abundantly expressed in microglia in the brain, is significantly up-regulated in the postmortem brain of Alzheimer’s disease patients and various neurodegenerative disease animal models. This supports the role of the P2X7R pathway in the progression of neurodegeneration. Blocking P2X7R using brilliant blue G, a P2X7R antagonist that can cross the blood–brain barrier, has been shown to result in the amelioration of neuropathology in various animal models. Taken together, these results raise the possibility that the P2X7R signaling pathway could be a therapeutic target for treating various neurodegenerative diseases.     

Deterministic center of pressure patterns characterize postural instability in Parkinson’s disease

Static posturographic recordings were obtained from six Parkinson’s patients and six age-matched, healthy control participants. The availability of vision and visuo-spatial cognitive load were manipulated. Postural sway patterns were analyzed using recurrence quantification analysis (RQA), which revealed differences in center of pressure (COP) dynamics between Parkinson’s and control participants. AP COP trajectories for the Parkinson’s group were not only significantly more variable than for the control group, but also exhibited distinct patterns of temporal dynamics. The visual manipulation did not differentially affect the two groups. No cognitive load effects were found. The results are generally consistent with the hypothesis that pathological physiological systems exhibit a tendency for less flexible, more deterministic dynamic patterns.     

Impact of subthalamic nucleus stimulation on the initiation of gait in Parkinson’s disease

The effects of subthalamic nucleus (STN) stimulation on the anticipatory postural actions associated with the initiation of gait were studied in ten patients with idiopathic Parkinson’s disease undergoing therapeutic deep brain stimulation. Kinematic, dynamic and electromyographic analysis was performed before and while subjects were starting gait in response to an external cue. Effects of STN stimulation on the standing posture preceding the go signal included significant improvement of the vertical alignment of the trunk and shank, decrease of the hip joint moment, backward shift of the center of pressure (CoP) and reduction of abnormal tonic and/or rhythmic activity in the thigh and leg muscles. Responses to bilateral STN stimulation were more consistent than those evoked by unilateral stimulation. Moreover, comparison between postural changes induced by STN stimulation applied prior to the gait initiation cue and during simple quiet standing revealed more significant responses in the former condition. Effects on the actual gait initiation process included shortening of the imbalance phase, larger backward/lateral displacement of CoP and more physiological expression of the underlying anticipatory muscular synergy. Additional changes were shortening of the unloading phase, shortening of the first-swing phase and increase in the length of the first step. Results demonstrate substantial influence of STN stimulation on functionally basic motor control mechanisms. In particular, the evidence of more significant responses upon attention-demanding conditions and the remarkable effects on postural programmes sub-serving feed-forward regulation of the onset of complex multijoint movements, suggests a consistent action on postural sub-systems relying on cognitive data processing and internal models of body mechanics.     

Selective degradation of p62 by autophagy

The autophagy–lysosome pathway is a highly conserved bulk degradation system in eukaryotes. During starvation, cytoplasmic constituents are non-selectively degraded by autophagy, and the resulting amino acids are utilized for cell survival. By taking advantage of mouse genetics, many physiological functions of mammalian autophagy have been uncovered. Growing lines of evidences have revealed the essential role of constitutive (or basal) autophagy in cellular homeostasis through its selectivity. p62, one of the selective substrates for autophagy, plays a key role in the formation of cytoplasmic proteinaceous inclusion, a hallmark of conformational diseases such as Alzheimer’s disease, Parkinson’s disease, and various chronic liver disorders. In this review, we discuss the physiological roles of the selective turnover of p62 by autophagy and their molecular mechanisms.