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The motor symptoms of both Parkinson's disease and focal dystonia arise from dysfunction of the basal ganglia, and are improved by pallidotomy or deep brain stimulation of the Globus Pallidus interna (GPi). However, Parkinson's disease is associated with a greater degree of basal ganglia-dependent learning impairment than dystonia. We attempt to understand this observation in terms of a comparison of the electrophysiology of the output of the basal ganglia between the two conditions. We use the natural experiment offered by Deep Brain Stimulation to compare GPi local field potential responses in subjects with Parkinson's disease compared to subjects with dystonia performing a forced-choice decision-making task with sensory feedback. In dystonic subjects, we found that auditory feedback was associated with the presence of high gamma oscillations nestled on a negative deflection, morphologically similar to sharp wave ripple complexes described in human rhinal cortex. These were not present in Parkinson's disease subjects. The temporal properties of the high gamma burst were modified by incorrect trial performance compared to correct trial performance. Both groups exhibited a robust low frequency response to 'incorrect' trial performance in dominant GPi but not non-dominant GPi at theta frequency. Our results suggest that cellular processes associated with striatum-dependent memory function may be selectively impaired in Parkinson's disease even if dopaminergic drugs are administered, but that error detection mechanisms are preserved.

We describe dropped head syndrome in a patient with Parkinson's disease receiving subthalamic nucleus deep brain stimulation (DBS). Posterior occipitocervical instrumented fusion after transarticular screw fixation of an odontoid fracture is shown and its rationale explained. Pedunculopontine nucleus DBS as treatment for fall-predominant Parkinson's disease, and globus pallidus interna DBS for dystonia-predominant Parkinson's disease, are discussed., ((c) 2009 Elsevier Ltd. All rights reserved.)

We measured reaction times during a stop-signal task while patients with Parkinson's disease were on and off unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). While reaction times to a "go" stimulus improved, there was no change in reaction times to the "stop" stimulus (SSRTs). However, changes in SSRTs induced by DBS were highly dependent on baseline SSRTs (measured off stimulation), with the greatest improvements being achieved by those with particularly slow reaction times. We therefore selected only those patients whose baseline SSRTs were within the limits of a control sample (N=10). In this group, SSRTs became slower when DBS was on. This finding suggests a role for the STN in response inhibition, which can be interrupted by DBS, observable only when more general improvements in Parkinson's function are minimised. We also compared the effects of unilateral left and right sided stimulation. We found a greater increase in SSRTs after DBS of the left STN.

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) is a novel neurosurgical therapy developed to address symptoms of gait freezing and postural instability in Parkinson's disease and related disorders. Here, we summarize our non-human primate and neuroimaging research of relevance to our surgical targeting of the PPN. We also describe our clinical experience of PPN DBS with greatest motor improvements achieved by stimulation at low frequencies.

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has recently been shown to effectively ameliorate medically intractable axial symptoms of Parkinson's disease (PD). The effects of DBS are not limited to the targeted structure, but will affect the distributed anatomical networks to which the target structure belongs. Therefore, understanding the anatomical connections of the PPN will help elucidate treatment effects. Furthermore, establishing the topography of cortical and sub-cortical connections of the PPN in the human brain could aid accurate targeting of critical pathways in DBS. This article summarizes the connections of the PPN and the distribution of these connections within this nucleus (topography) as previously determined using diffusion tensor imaging (DTI) in healthy human volunteers and in a primate Macaca mulatta brain. These findings highlight DTI as a useful tool for surgical targeting for DBS of the PPN, and also show that DTI can be used to accurately probe the anatomy of the human and monkey brain in vivo.

Scientific research involving non-human primates has contributed towards many advances in medicine and surgery. This review discusses its role in the progress made towards our understanding of Parkinson's disease and its treatment. Established medical treatments like dopamine agonists continue to need primate models to assess their efficacy, safety, and mechanism of action. The recently developed treatment of deep brain stimulation of the subthalamic nucleus required validation in primates before entering the clinic. Controversies surrounding future treatments such as gene therapy show the need for properly evaluated preclinical research using appropriate animal models before progression to clinical trials. Research on primates has played--and continues to play--a crucial part in deepening our understanding of Parkinson's disease, improving current therapies, and developing new treatments that are both safe and effective. In animal research, the "three Rs" of humane technique--reduction, refinement, and replacement--should be adhered to.

Deep brain stimulation (DBS) is used to treat a variety of severe medically intractable movement disorders, including Parkinson's disease, tremor and dystonia. There have been few studies examining the effect of chronic DBS on the brains of Parkinson's disease patients. Most of these post mortem studies concluded that chronic DBS caused mild gliosis around the lead track and did not damage brain tissue. There have been no similar histopathological studies on brains from dystonic patients who have undergone DBS. In this study, our objective was to discover whether tissue would be attached to DBS electrodes removed from patients for routine clinical reasons. We hoped that by examining explanted DBS electrodes using scanning (SEM) and/or transmission (TEM) electron microscopy we might visualize any attached tissue and thus understand the electrode-human brain tissue interaction more accurately. Initially, SEM was performed on one control DBS electrode that had not been implanted. Then 21 (one subthalamic nucleus and 20 globus pallidus internus) explanted DBS electrodes were prepared, after fixation in 3% glutaraldehyde, for SEM (n = 9) or TEM (n = 10), or both (n = 2), according to departmental protocol. The electrodes were sourced from two patients with Parkinson's disease, one with myoclonic dystonia, two with cervical dystonia and five with primary generalized dystonia, and had been in situ for 11 and 31 months (Parkinson's disease), 16 months (myoclonic dystonia), 14 and 24 months (cervical dystonia) and 3-24 months (primary generalized dystonia). Our results showed that a foreign body multinucleate giant cell-type reaction was present in all TEM samples and in SEM samples, prewashed to remove surface blood and fibrin, regardless of the diagnosis. Some of the giant cells were >100 microm in diameter and might have originated from either fusion of parenchymal microglia, resident perivascular macrophage precursors and/or monocytes/macrophages invading from the blood stream. The presence of mononuclear macrophages containing lysosomes and sometimes having conspicuous filopodia was detected by TEM. Both types of cell contained highly electron-dense inclusions, which probably represent phagocytosed material. Similar material, the exact nature of which is unknown, was also seen in the vicinity of these cells. This reaction was present irrespective of the duration of implantation and may be a response to the polyurethane component of the electrodes' surface coat. These findings may be relevant to our understanding of the time course of the clinical response to DBS in Parkinson's disease and various forms of dystonia, as well as contributing to the design characteristics of future DBS electrodes.

With the rapid increase in provision of deep brain stimulation for Parkinson's disease, the efficacy of pallidotomy in symptom alleviation appears to be increasingly ignored. We demonstrate that lesional surgery is effective with benefit over a significant period of time with very significant societal cost savings. Such studies are essential for future planning of services so that maximum numbers of patients can benefit from surgery, both lesional and neuromodulation, as deemed appropriate.

Objectives: To investigate the oscillatory activity in the Parkinsonian subthalamic nucleus using the macro-electrodes for deep brain stimulation., Methods: During bilateral deep brain stimulating electrode implantation, spontaneous and evoked field potentials were recorded from the subthalamic nucleus (STN) in two patients with Parkinson's disease (PD) during spontaneous resting tremor, passive manipulation of the wrist, and following electrical stimulation of the contralateral STN., Results: Frequency analysis of the STN field potentials recorded during spontaneous resting tremor showed significant coherence with electromyographic activity in the contralateral arm, suggesting a close involvement of the STN in the generation of resting tremor in PD. The STN responded to passive movement of the contralateral wrist, but not to ipsilateral movement. High frequency (100 Hz) electrical stimulation of the STN induced tremor (4 Hz) in both forearms, and also oscillation of the contralateral STN (4 Hz). In contrast, low frequency (5 Hz) stimulation induced contralateral arrhythmic involuntary movement (3 Hz), but without altering the contralateral STN activity., Conclusions: We propose that the functional connection between the STN and arm muscles is mainly contralateral, but cross talk may occur between bilateral STN via a frequency-dependent pathway.

To investigate the response to visual feedback of involuntary movements which have a frequency composition similar to cerebellar tremor but are not caused by cerebellar damage, we have tested six advanced Parkinson's disease (PD) patients with drug-induced dyskinetic movements using visually guided wrist tracking tasks. Tracking performance was assessed under three visual conditions: (1) both guiding target and movement cursor were displayed continuously; (2) the target display was turned off for the second half of each trial; or (3) the cursor display, but not the target, was turned off for the second half of each trial. The response to visual feedback of drug-induced dyskinetic movements at 1-5 Hz in these advanced PD patients were significantly increased than in normal controls. This suggests that increased response to visual feedback might be a common feature of low frequency involuntary movements and not directly caused by cerebellar damages.

Ever since it was demonstrated about twenty years ago by two independent groups (Aziz et al. and Bergman et al.) that the cardinal clinical features of MPTP-induced Parkinson's disease (PD) in non-human primate models can be alleviated by lesions of the subthalamic nucleus (STN), this structure has been the focus of interest for functional neurosurgeons involved in the treatment of PD. Initially lesioning and later chronic high frequency stimulation of the STN has become the standard surgical target of akinetic PD. In this brief report we present our experience with 14 STN lesions (8 unilateral and 3 bilateral) confirmed by post-operative imaging. We found significant improvement in OFF rigidity and in ON tremor following unilateral lesions. The major complications were speech disturbance and L-Dopa resistant limb dystonia. Functional disability scores showed inconsistent reduction. There was insufficient data to comment on the significance of bilateral lesions; however, there was a similar pattern of improvement in tremor and speech disturbance. In addition, there was worsening of gait. We comment on the lower degree of improvement in motor scores in our series compared to the few others in recent literature and stress that even in these studies the UPDRS benefits did not translate directly into functional benefit for the patients., (Copyright 2002 S. Karger AG, Basel)

The small size and surrounding neuronal structures and fibre tracts make the STN a difficult stereotactic target. In this article we present the technique used by us to target the STN. Our combined experience from two centres comprises 18 lesions and 27 stimulator implants in the STN. Our criteria for patient selection and the use of MRI, frame-on CT and volumetric image fusion are presented. The role of a movement disorder specialist neurologist in the operating theatre, local field potential recording, impedance monitoring, macrostimulation, post-operative CT/MRI and test stimulation are detailed., (Copyright 2002 S. Karger AG, Basel)

Visual feedback is one of the key elements in on-line control of smooth manual tracking. To in- vestigate the effects basal ganglia dysfunction have on visual feedback control, we have tested six advanced Parkinson's disease (PD) patients in comparison with normal controls using visually guided wrist tracking tasks. Tracking performance was assessed under three visual conditions: (1) both guiding target and movement cursor were displayed continuously; (2) the target display was turned off for the second half of each trial; or (3) the cursor display, but not the target, was turned off for the second half of each trial. Thus, for the second half of each trial under conditions 2 and 3, no visual feedback of the relationship between the target and the cursor was available. Results showed that although PD patients had significantly larger tracking errors than controls, and errors significantly increased in both PD patients and controls after withdrawing either visual cue, increases in tracking errors in PD were not significantly different from those in controls. Nor were any significant changes found in the frequency (6-8 Hz) or magnitude of the PD patient's action tremor after withdrawing visual feedback. These results suggest that on-line movement control of wrist tracking movements in advanced PD is not especially reliant on visual feedback. In conjunction with our previous study of multiple sclerosis (MS) patients, the present results confirm that the basal ganglia is less involved in visual guidance of smooth manual tracking than the cerebellar circuits.