[Show abstract][Hide abstract] ABSTRACT: We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson's disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case.
All three G51D patients were clinically characterised by parkinsonism, dementia, visual hallucinations, autonomic dysfunction and pyramidal signs with variable age at disease onset and levodopa response. The H50Q SNCA mutation case had a clinical picture that mimicked late-onset idiopathic PD with a good and sustained levodopa response. The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism. Detailed post-mortem neuropathological analysis was performed in all cases. All three G51D cases had abundant α-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal α-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had α-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated α-synuclein was present in all inclusions types in G51D cases but was more restricted in SNCA duplication and H50Q mutation. Inclusions were also immunoreactive for the 5G4 antibody indicating their highly aggregated and likely fibrillar state.
Our characterisation of the clinical and neuropathological features of the present small series of G51D SNCA mutation cases should aid the recognition of this clinico-pathological entity. The neuropathological features of these cases consistently share characteristics of PD and MSA and are distinct from PD patients carrying the H50Q or SNCA duplication.
[Show abstract][Hide abstract] ABSTRACT: Introduction & objectives:
Adaptive deep brain stimulation (aDBS) uses feedback from brain signals to guide stimulation. A recent acute trial of unilateral aDBS showed that aDBS can lead to substantial improvements in contralateral hemibody Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and may be superior to conventional continuous DBS in Parkinson's disease (PD). We test whether potential benefits are retained with bilateral aDBS and in the face of concurrent medication.
We applied bilateral aDBS in 4 patients with PD undergoing DBS of the subthalamic nucleus. aDBS was delivered bilaterally with independent triggering of stimulation according to the amplitude of β activity at the corresponding electrode. Mean stimulation voltage was 3.0±0.1 volts. Motor assessments consisted of double-blinded video-taped motor UPDRS scores that included both limb and axial features.
UPDRS scores were 43% (p=0.04; Cohen's d=1.62) better with aDBS than without stimulation. Motor improvement with aDBS occurred despite an average time on stimulation (ToS) of only 45%. Levodopa was well tolerated during aDBS and led to further reductions in ToS.
Bilateral aDBS can improve both axial and limb symptoms and can track the need for stimulation across drug states.
Journal of neurology, neurosurgery, and psychiatry 10/2015; DOI:10.1136/jnnp-2015-310972 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: When choosing between two options, sufficient accumulation of information is required to favor one of the options over the other, before a decision is finally reached. To establish the effect of dopaminergic medication on the rate of accumulation of information, decision thresholds and speed–accuracy trade-offs, we tested 14 patients with Parkinson's disease (PD) on and off dopaminergic medication and 14 age-matched healthy controls on two versions of the moving-dots task. One version manipulated the level of task difficulty and hence effort required for decision-making and the other the urgency, requiring decision-making under speed vs. accuracy instructions. The drift diffusion model was fitted to the behavioral data.
[Show abstract][Hide abstract] ABSTRACT: Magnetic resonance imaging (MRI)-verified deep brain stimulation relies on the correct interpretation of stereotactic imaging documenting lead location in relation to visible anatomic target. However, it has been suggested that local signal distortion from the lead itself renders its depiction on MRI unreliable.
To compare lead location on stereotactic MRI with subsequent location of its brain track after removal.
Patients underwent deep brain stimulation with the use of MRI-guided and MRI-verified Leksell frame approach. Infection or suboptimal efficacy required lead removal and subsequent reimplantation by using the same technique. Postimplantation stereotactic MR images were analyzed. Lateral (x) and anteroposterior (y) distances from midcommissural point to center of the lead hypointensity were recorded at the anterior commissure-posterior commissure plane (pallidal electrode) or z = -4 (subthalamic electrode). Stereotactic MRI before the second procedure, x and y distances from the center of the visible lead track hypointensity to midcommissural point were independently recorded. Vectorial distance from center of the lead hypointensity to the center of its track was calculated.
Sixteen electrode tracks were studied in 10 patients. Mean differences between lead artifact location and lead track location were: x coordinate 0.4 mm ± 0.2; y coordinate 0.6 mm ± 0.3. Mean vectorial distance was 0.7 mm ± 0.2.
Stereotactic distance between lead location and subsequent brain track location on MRI was small. The mean discrepancy was approximately half the deep brain stimulation lead width. This suggests that lead hypointensity seen on postimplantation MRI is indeed an accurate representation of its real location within deep brain structures.
AC, anterior commissureDBS, deep brain stimulationPC, posterior commissurePPN, pedunculopontine nucleusSTN, subthalamic nucleus.
[Show abstract][Hide abstract] ABSTRACT: Deep brain stimulation (DBS) is an established treatment for patients with movement disorders. Patients receiving chronic DBS provide a unique opportunity to explore the underlying mechanisms of DBS using functional MRI. It has been shown that the main safety concern with MRI in these patients is heating at the electrode tips - which can be minimised with strict adherence to a supervised acquisition protocol using a head-transmit/receive coil at 1.5T. MRI using the body-transmit coil with a multi-channel receive head coil has a number of potential advantages including an improved signal-to-noise ratio.
We compared the safety of cranial MRI in an in vitro model of bilateral DBS using both head-transmit and body-transmit coils. We performed fibre-optic thermometry at a Medtronic ActivaPC device and Medtronic 3389 electrodes during turbo-spin echo (TSE) MRI using both coil arrangements at 1.5T and 3T, in addition to gradient-echo echo-planar fMRI exposure at 1.5T. Finally, we investigated the effect of transmit-coil choice on DBS stimulus delivery during MRI.
Temperature increases were consistently largest at the electrode tips. Changing from head- to body-transmit coil significantly increased the electrode temperature elevation during TSE scans with scanner-reported head SAR 0.2W/kg from 0.45°C to 0.79°C (p<0.001) at 1.5T, and from 1.25°C to 1.44°C (p<0.001) at 3T. The position of the phantom relative to the body coil significantly impacted on electrode heating at 1.5T; however, the greatest heating observed in any position tested remained <1°C at this field strength.
We conclude that (1) with our specific hardware and SAR-limited protocol, body-transmit cranial MRI at 1.5T does not produce heating exceeding international guidelines, even in cases of poorly positioned patients, (2) cranial MRI at 3T can readily produce heating exceeding international guidelines, (3) patients with ActivaPC Medtronic systems are safe to be recruited to future fMRI experiments performed under the specific conditions defined by our protocol, with no likelihood of confound by inappropriate stimulus delivery.
PLoS ONE 06/2015; 10(6):e0129077. DOI:10.1371/journal.pone.0129077 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Modern deep brain stimulation (DBS) has become a routine therapy for patients with movement disorders such as Parkinson’s disease, generalized or segmental dystonia and for multiple forms of tremor. Growing numbers of publications also report beneficial effects in other movement disorders such as Tourette’s syndrome, various forms of chorea and DBS is even being studied for Parkinson’s-related dementia. While exerting remarkable effects on many motor symptoms, DBS does not restore normal neurophysiology and therefore may also have undesirable side effects including speech and gait deterioration. Furthermore, its efficacy might be compromised in the long term, due to progression of the underlying disease. Various programming strategies have been studied to try and address these issues, e.g., the use of low-frequency rather than high-frequency stimulation or the targeting of alternative brain structures such as the pedunculopontine nucleus. In addition, further technical developments will soon provide clinicians with an expanded choice of hardware such as segmented electrodes allowing for a steering of the current to optimize beneficial effects and reduce side effects as well as the possibility of adaptive stimulation systems based on closed-loop concepts with or without accompanying advances in programming and imaging software. In the present article, we will provide an update on the most recent achievements and discoveries relevant to the application of DBS in the treatment of movement disorder patients and give an outlook on future clinical and technical developments.
Journal of Neurology 06/2015; DOI:10.1007/s00415-015-7790-8 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The fronto-striatal circuits are considered to mediate inhibitory control over action. The aim of this study was to investigate the contribution of the internal segment of the pallidum (GPi), one of the final output pathways from the basal ganglia to the cortex, in inhibition. We examined the effect of deep brain stimulation (DBS) of the GPi (GPi-DBS) in patients with Parkinson's disease who performed a conditional stop signal task, with DBS on and off. Modulation of GPi activity was associated with significantly faster Go reaction times with DBS on than off, but stop signal reaction times were not altered. Application of the drift diffusion model indicated that GPi-DBS was associated with significantly lower response thresholds compared to GPi-DBS off. However, the drift rate was significantly lower than healthy controls with both GPi-DBS on and off. These results suggest that the GPi plays a crucial role in the 'Go' pathway, perhaps facilitating reaching the required threshold to initiate actions. However, GPi-DBS does not alter the functioning of the indirect 'NoGo' pathway, and other basal ganglia nuclei, such as the STN, may play a greater role in reactive response inhibition and conflict resolution.
Journal of Neurology 05/2015; 262(7). DOI:10.1007/s00415-015-7768-6 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: It has been proposed that the subthalamic nucleus (STN) modulates response thresholds and speed-accuracy trade-offs (SAT). More specifically, in situations of conflict, the STN is ordinarily considered to raise response thresholds, preventing premature responses and allowing time for the accumulation of information to occur before a response is selected.
Objectives: We tested the hypothesis that acting under time pressure of speed instructions would be associated with lower response thresholds and fast, errorful responses for patients with Parkinson’s disease with deep brain stimulation (DBS) of the STN on compared to DBS off.
Methods: The ‘moving dots’ motion discrimination and perceptual decision-making task was used to assess SATs under both speed and accuracy instructions by measuring reaction times and errors. We assessed twelve patients with bilateral STN-DBS and twelve age-matched healthy controls. Participants completed the task twice; patients with stimulation on or off, with order counterbalanced.
Results: All participants were able to modulate reaction times according to speed and accuracy instructions. Stimulation of the STN was associated with significantly and differentially faster RTs, but more errors under speed instructions relative to STN-DBS off. Application of the drift diffusion model showed that under speed instructions, STN stimulation resulted in lower response thresholds relative to when the stimulators were off.
Conclusions: Such STN stimulation-induced ‘impulsivity’, reflected by fast and errorful responses when acting under time pressure, may contribute to the development of post-operative psychiatric problems including de novo impulse control disorders in some patients. These results support involvement of the STN in SATs.
Keywords: Parkinson’s disease; subthalamic nucleus; deep brain stimulation, speed-accuracy trade-offs; response threshold, impulsivity
The 2015 British Neuropsychological Society Meeting, Clinical Neurosciences Centre, 33 Queen Square, London, WC1N 3BG; 03/2015
[Show abstract][Hide abstract] ABSTRACT: Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) ameliorates the motor symptoms of Parkinson's disease (PD). However, some aspects of executive control are impaired with STN DBS. Objective: We tested the prediction that (i) STN-DBS interferes with switching from automatic to controlled processing during fast-paced random number generation (RNG) (ii) STN-DBS-induced cognitive control changes are load-dependent. Methods: Fifteen PD patients with bilateral STN-DBS performed paced-RNG, under three levels of cognitive load synchronised with a pacing stimulus presented at 1, 0.5 and 0.33 Hz (faster rates require greater cognitive control), with DBS on or off. Measures of output randomness were calculated. Countscore 1 (CS1) indicates habitual counting in steps of one (CS1). Countscore 2 (CS2) indicates a more controlled strategy of counting in twos. Results: The fastest rate was associated with an increased CS1 score with STN-DBS on compared to off. At the slowest rate, patients had higher CS2 scores with DBS off than on, such that the differences between CS1 and CS2 scores disappeared. Conclusions: We provide evidence for a load-dependent effect of STN-DBS on paced RNG in PD. Patients could switch to more controlled RNG strategies during conditions of low cognitive load at slower rates only when the STN stimulators were off, but when STN stimulation was on, they engaged in more automatic habitual counting under increased cognitive load. These findings are consistent with the proposal that the STN implements a switch signal from the medial frontal cortex which enables a shift from automatic to controlled processing.
[Show abstract][Hide abstract] ABSTRACT: Objectives
The aim of this study was to investigate the deep brain stimulation (DBS) electric field distribution in proton-density MRI scans visualizing the globus pallidus internus (GPi) of patients with Gilles de la Tourette syndrome (GTS), along with its relation to the anatomy.Methods
Patient-specific brain tissue models (n = 7) with bilateral DBS electrodes in the GPi were set up using the finite element method in five patients who had undergone stereotactic proton-density MRI-guided surgery and showed variable improvement with DBS. Simulations (n = 27) of the electric field were performed and the results visualized on the respective preoperative stereotactic MRI scans. The mean electric field volumes (n = 81) within the 0.1, 0.15, and 0.2 V/mm isosurfaces were calculated and compared with the anatomy.ResultsVisualization of the simulated electric field confirmed that the anteromedial limbic GPi was the main stimulated target for four of the patients and the posteromedial sensorimotor GPi for one. Larger volumes extended asymmetrically, with parts of fields stretching into the lamina between GPi and globus pallidus externus and into the internal capsule. There was a high correlation (r = 0.994, n = 54) between volumes and brain sides, but with a systematic shift toward the right side, especially for the larger volumes. Simulations with homogeneous tissue models showed no differences.Conclusions
Patient-specific DBS electric field simulations in the GPi as visualized on proton-density MR scans can be implemented in patients with GTS. Visualization of electric fields together with stereotactic thin-slice MRI can provide further support when predicting anatomical structures possibly influenced by DBS in this complex disorder.
[Show abstract][Hide abstract] ABSTRACT: Tremor is a cardinal feature of Parkinson's disease and essential tremor, the two most common movement disorders. Yet, the mechanisms underlying tremor generation remain largely unknown. We hypothesized that driving deep brain stimulation electrodes at a frequency closely matching the patient's own tremor frequency should interact with neural activity responsible for tremor, and that the effect of stimulation on tremor should reveal the role of different deep brain stimulation targets in tremor generation. Moreover, tremor responses to stimulation might reveal pathophysiological differences between parkinsonian and essential tremor circuits. Accordingly, we stimulated 15 patients with Parkinson's disease with either thalamic or subthalamic electrodes (13 male and two female patients, age: 50-77 years) and 10 patients with essential tremor with thalamic electrodes (nine male and one female patients, age: 34-74 years). Stimulation at near-to tremor frequency entrained tremor in all three patient groups (ventrolateral thalamic stimulation in Parkinson's disease, P = 0.0078, subthalamic stimulation in Parkinson's disease, P = 0.0312; ventrolateral thalamic stimulation in essential tremor, P = 0.0137; two-tailed paired Wilcoxon signed-rank tests). However, only ventrolateral thalamic stimulation in essential tremor modulated postural tremor amplitude according to the timing of stimulation pulses with respect to the tremor cycle (e.g. P = 0.0002 for tremor amplification, two-tailed Wilcoxon rank sum test). Parkinsonian rest and essential postural tremor severity (i.e. tremor amplitude) differed in their relative tolerance to spontaneous changes in tremor frequency when stimulation was not applied. Specifically, the amplitude of parkinsonian rest tremor remained unchanged despite spontaneous changes in tremor frequency, whereas that of essential postural tremor reduced when tremor frequency departed from median values. Based on these results we conclude that parkinsonian rest tremor is driven by a neural network, which includes the subthalamic nucleus and ventrolateral thalamus and has broad frequency-amplitude tolerance. We propose that it is this tolerance to changes in tremor frequency that dictates that parkinsonian rest tremor may be significantly entrained by low frequency stimulation without stimulation timing-dependent amplitude modulation. In contrast, the circuit influenced by low frequency thalamic stimulation in essential tremor has a narrower frequency-amplitude tolerance so that tremor entrainment through extrinsic driving is necessarily accompanied by amplitude modulation. Such differences in parkinsonian rest and essential tremor will be important in selecting future strategies for closed loop deep brain stimulation for tremor control.