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1.  Deep brain stimulation in childhood: an effective treatment for early onset idiopathic generalised dystonia 
Archives of Disease in Childhood  2007;92(8):708-711.
Background
Early onset idiopathic generalised dystonia is a progressive and profoundly disabling condition. Medical treatment may ameliorate symptoms. However, many children have profound, intractable disability including the loss of ambulation and speech, and difficulties with feeding. Following the failure of medical management, deep brain stimulation (DBS) of the globus pallidus internus (GPi) has emerged as an alternative treatment for the disorder.
Methods
We describe four children who presented with dystonia.
Results
Following the failure of a range of medical therapies, DBS systems were implanted in the GPi in an attempt to ameliorate the children's disabilities. All children found dystonic movements to be less disabling following surgery. Compared with preoperative Burke, Fahn and Marsden Dystonia Rating Scale scores, postoperative scores at 6 months were improved.
Conclusions
DBS is effective in improving symptoms and function in children with idiopathic dystonia refractory to medical treatment. Whilst surgery is complex and can be associated with intraoperative and postoperative complications, this intervention should be considered following the failure of medical therapy.
doi:10.1136/adc.2006.095380
PMCID: PMC2083907  PMID: 17460025
generalised dystonia; torsion dystonia; deep brain stimulation; globus pallidus internus (GPi); neurodisability
2.  Adaptive Deep Brain Stimulation In Advanced Parkinson Disease 
Annals of Neurology  2013;74(3):449-457.
Objective: Brain–computer interfaces (BCIs) could potentially be used to interact with pathological brain signals to intervene and ameliorate their effects in disease states. Here, we provide proof-of-principle of this approach by using a BCI to interpret pathological brain activity in patients with advanced Parkinson disease (PD) and to use this feedback to control when therapeutic deep brain stimulation (DBS) is delivered. Our goal was to demonstrate that by personalizing and optimizing stimulation in real time, we could improve on both the efficacy and efficiency of conventional continuous DBS.
Methods: We tested BCI-controlled adaptive DBS (aDBS) of the subthalamic nucleus in 8 PD patients. Feedback was provided by processing of the local field potentials recorded directly from the stimulation electrodes. The results were compared to no stimulation, conventional continuous stimulation (cDBS), and random intermittent stimulation. Both unblinded and blinded clinical assessments of motor effect were performed using the Unified Parkinson's Disease Rating Scale.
Results: Motor scores improved by 66% (unblinded) and 50% (blinded) during aDBS, which were 29% (p = 0.03) and 27% (p = 0.005) better than cDBS, respectively. These improvements were achieved with a 56% reduction in stimulation time compared to cDBS, and a corresponding reduction in energy requirements (p < 0.001). aDBS was also more effective than no stimulation and random intermittent stimulation.
Interpretation BCI-controlled DBS is tractable and can be more efficient and efficacious than conventional continuous neuromodulation for PD. Ann Neurol 2013;74:449–457
doi:10.1002/ana.23951
PMCID: PMC3886292  PMID: 23852650
3.  Ready for action: a role for the human midbrain in responding to infant vocalizations 
Infant vocalizations are among the most biologically salient sounds in the environment and can draw the listener to the infant rapidly in both times of distress and joy. A region of the midbrain, the periaqueductal gray (PAG), has long been implicated in the control of urgent, survival-related behaviours. To test for PAG involvement in the processing of infant vocalizations, we recorded local field potentials from macroelectrodes implanted in this region in four adults who had undergone deep brain stimulation. We found a significant difference occurring as early as 49 ms after hearing a sound in activity recorded from the PAG in response to infant vocalizations compared with constructed control sounds and adult and animal affective vocalizations. This difference was not present in recordings from thalamic electrodes implanted in three of the patients. Time frequency analyses revealed distinct patterns of activity in the PAG for infant vocalisations, constructed control sounds and adult and animal vocalisations. These results suggest that human infant vocalizations can be discriminated from other emotional or acoustically similar sounds early in the auditory pathway. We propose that this specific, rapid activity in response to infant vocalizations may reflect the initiation of a state of heightened alertness necessary to instigate protective caregiving.
doi:10.1093/scan/nst076
PMCID: PMC4090964  PMID: 23720574
periaqueductal gray; infant; parenting; local field potentials; deep brain stimulation; midbrain
4.  A role for the subthalamic nucleus in response inhibition during conflict 
The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or if higher cognitive centres are alone responsible. We show stimulus driven desychronisation in the beta-band (15 – 35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials - where response times were elongated due to the Stroop effect - a resynchronisation was seen in the beta-band prior to response. Crucially, in the incongruent trials during which the participant was unable to withhold the pre-potent response this resynchronisation occurred after response onset. We suggest that this beta-band resynchronisation pauses the motor system until conflict can be resolved.
doi:10.1523/JNEUROSCI.2259-12.2012
PMCID: PMC3492743  PMID: 23015430
Beta oscillatory activity; deep brain stimulation; basal ganglia; speech; cognitive control
5.  Tremor Suppression by Rhythmic Transcranial Current Stimulation 
Current Biology  2013;23(5):436-440.
Summary
Tremor can dominate Parkinson’s disease and yet responds less well to dopaminergic medications than do other cardinal symptoms of this condition [1, 2]. Deep brain stimulation can provide striking tremor relief, but the introduction of stimulating electrodes deep in the substance of the brain carries significant risks, including those of hemorrhage [3]. Here, we pioneer an alternative approach in which we noninvasively apply transcranial alternating current stimulation (TACS) over the motor cortex [4, 5] to induce phase cancellation of the rest tremor rhythm. We first identify the timing of cortical oscillations responsible for rest tremor in the periphery by delivering tremor-frequency stimulation over motor cortex but do not couple this stimulation to the on-going tremor—instead, the rhythms simply “drift” in and out of phase alignment with one another. Slow alternating periods of phase cancellation and reinforcement result, informing on the phase alignments that induce the greatest change in tremor amplitude. Next, we deliver stimulation at these specified phase alignments to demonstrate controlled suppression of the on-going tremor. With this technique we can achieve almost 50% average reduction in resting tremor amplitude and in so doing form the basis of a closed-loop tremor-suppression therapy that could be extended to other oscillopathies.
Graphical Abstract
Highlights
► Phase-cancelling cortical stimulation attenuates Parkinsonian tremor ► Prolonged stimulation may invoke adaptive mechanisms ► Phase cancellation may provide a generic treatment approach to oscillopathies ► TACS provides a convenient probe of cortical circuit dynamics in humans
doi:10.1016/j.cub.2013.01.068
PMCID: PMC3629558  PMID: 23416101
6.  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.
doi:10.1007/s00221-012-3107-7
PMCID: PMC3366185  PMID: 22580572
Parkinson’s disease; Rigidity; Oscillations; Beta; Deep brain stimulation
7.  A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation 
Brain  2012;135(5):1446-1454.
Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson’s disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients’ usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.
doi:10.1093/brain/aws039
PMCID: PMC3338924  PMID: 22396391
Parkinson’s disease; gait freezing; deep brain stimulation; pedunculopontine nucleus
8.  Driving Oscillatory Activity in the Human Cortex Enhances Motor Performance 
Current Biology  2012;22(5):403-407.
Summary
Voluntary movement is accompanied by changes in the degree to which neurons in the brain synchronize their activity within discrete frequency ranges. Two patterns of movement-related oscillatory activity stand out in human cortical motor areas. Activity in the beta frequency (15–30 Hz) band is prominent during tonic contractions but is attenuated prior to and during voluntary movement [1]. Without such attenuation, movement may be slowed, leading to the suggestion that beta activity promotes postural and tonic contraction, possibly at a cost to the generation of new movements [2, 3]. In contrast, activity in the gamma (60–90 Hz) band increases during movement [4]. The direction of change suggests that gamma activity might facilitate motor processing. In correspondence with this, increased frontal gamma activity is related with reduced reaction times [5]. Yet the possibility remains that these functional correlations reflect an epiphenomenal rather than causal relationship. Here we provide strong evidence that oscillatory activities at the cortical level are mechanistically involved in determining motor behavior and can even improve performance. By driving cortical oscillations using noninvasive electrical stimulation, we show opposing effects at beta and gamma frequencies and interactions with motor task that reveal the potential quantitative importance of oscillations in motor behavior.
Highlights
► Cortical driving at 20 and 70 Hz slows and speeds voluntary force generation ► Performance can be enhanced even during contractions made as fast as possible ► Scale of effects of cortical driving depend on the nature of the cued motor task
doi:10.1016/j.cub.2012.01.024
PMCID: PMC3343257  PMID: 22305755
9.  Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism 
Brain  2012;135(1):148-160.
The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinson's disease, pedunculopontine nucleus stimulation is an emerging treatment for gait freezing. Local field potentials recorded from pedunculopontine nucleus electrodes in such patients have demonstrated oscillations in the alpha and beta frequency bands, reactive to self-paced movement. Whether these oscillations are topographically organized or relevant to locomotion is unknown. Here, we recorded local field potentials from the pedunculopontine nucleus in parkinsonian patients during rest and unconstrained walking. Relative gait speed was assessed with trunk accelerometry. Peaks of alpha power were present at rest and during gait, when they correlated with gait speed. Gait freezing was associated with attenuation of alpha activity. Beta peaks were less consistently observed across rest and gait, and did not correlate with gait speed. Alpha power was maximal in the caudal pedunculopontine nucleus region and beta power was maximal rostrally. These results indicate a topographic distribution of neuronal activity in the pedunculopontine nucleus region and concur with animal data suggesting that the caudal subregion has particular relevance to gait. Alpha synchronization, proposed to suppress ‘task irrelevant’ distraction, has previously been demonstrated to correlate with performance of cognitive tasks. Here, we demonstrate a correlation between alpha oscillations and improved gait performance. The results raise the possibility that stimulation of caudal and rostral pedunculopontine nucleus regions may differ in their clinical effects.
doi:10.1093/brain/awr315
PMCID: PMC3267984  PMID: 22232591
Parkinson's disease; gait freezing; pedunculopontine nucleus; deep brain stimulation; neuronal oscillations
10.  Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner 
Neuroimage  2011;57(1-4):167-181.
Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and “gold standard” histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.
Research highlights
► Acquisition and processing protocols for diffusion MRI of post-mortem human brains. ► Effect of post-mortem and scan intervals on diffusion indices. ► Tractography in post-mortem human brains. ► Radial diffusion anisotropy in cortical gray matter.
doi:10.1016/j.neuroimage.2011.03.070
PMCID: PMC3115068  PMID: 21473920
Diffusion tensor imaging; Tractography; Post mortem; Human; Brain
11.  A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation 
Brain  2011;134(7):2085-2095.
Gait freezing and postural instability are disabling features of Parkinsonian disorders, treatable with pedunculopontine nucleus stimulation. Both features are considered deficits of proximal and axial musculature, innervated predominantly by reticulospinal pathways and tend to manifest when gait and posture require adjustment. Adjustments to gait and posture are amenable to pre-preparation and rapid triggered release. Experimentally, such accelerated release can be elicited by loud auditory stimuli—a phenomenon known as ‘StartReact’. We observed StartReact in healthy and Parkinsonian controls. However, StartReact was absent in Parkinsonian patients with severe gait freezing and postural instability. Pedunculopontine nucleus stimulation restored StartReact proximally and proximal reaction times to loud stimuli correlated with gait and postural disturbance. These findings suggest a relative block to triggered, pre-prepared movement in gait freezing and postural instability, relieved by pedunculopontine nucleus stimulation.
doi:10.1093/brain/awr131
PMCID: PMC3122373  PMID: 21705424
deep brain stimulation; gait freezing; Parkinson’s disease; pedunculopontine nucleus; StartReact
12.  Balancing the Brain: Resting State Networks and Deep Brain Stimulation 
Over the last three decades, large numbers of patients with otherwise treatment-resistant disorders have been helped by deep brain stimulation (DBS), yet a full scientific understanding of the underlying neural mechanisms is still missing. We have previously proposed that efficacious DBS works by restoring the balance of the brain's resting state networks. Here, we extend this proposal by reviewing how detailed investigations of the highly coherent functional and structural brain networks in health and disease (such as Parkinson's) have the potential not only to increase our understanding of fundamental brain function but of how best to modulate the balance. In particular, some of the newly identified hubs and connectors within and between resting state networks could become important new targets for DBS, including potentially in neuropsychiatric disorders. At the same time, it is of essence to consider the ethical implications of this perspective.
doi:10.3389/fnint.2011.00008
PMCID: PMC3088866  PMID: 21577250
resting state networks; oscillations; spontaneous activity; affective disorders; movement disorders
13.  A Specific and Rapid Neural Signature for Parental Instinct 
PLoS ONE  2008;3(2):e1664.
Darwin originally pointed out that there is something about infants which prompts adults to respond to and care for them, in order to increase individual fitness, i.e. reproductive success, via increased survivorship of one's own offspring. Lorenz proposed that it is the specific structure of the infant face that serves to elicit these parental responses, but the biological basis for this remains elusive. Here, we investigated whether adults show specific brain responses to unfamiliar infant faces compared to adult faces, where the infant and adult faces had been carefully matched across the two groups for emotional valence and arousal, as well as size and luminosity. The faces also matched closely in terms of attractiveness. Using magnetoencephalography (MEG) in adults, we found that highly specific brain activity occurred within a seventh of a second in response to unfamiliar infant faces but not to adult faces. This activity occurred in the medial orbitofrontal cortex (mOFC), an area implicated in reward behaviour, suggesting for the first time a neural basis for this vital evolutionary process. We found a peak in activity first in mOFC and then in the right fusiform face area (FFA). In mOFC the first significant peak (p<0.001) in differences in power between infant and adult faces was found at around 130 ms in the 10–15 Hz band. These early differences were not found in the FFA. In contrast, differences in power were found later, at around 165 ms, in a different band (20–25 Hz) in the right FFA, suggesting a feedback effect from mOFC. These findings provide evidence in humans of a potential brain basis for the “innate releasing mechanisms” described by Lorenz for affection and nurturing of young infants. This has potentially important clinical applications in relation to postnatal depression, and could provide opportunities for early identification of families at risk.
doi:10.1371/journal.pone.0001664
PMCID: PMC2244707  PMID: 18301742
14.  Surgical insights into Parkinson's disease 
Surgery for Parkinson's disease was popularized in the midtwentieth century before the advent of effective medical therapies. Early lesioning treatments contributed to our understanding of the functional anatomy of Parkinson's disease. Observations of the limitations and long-term complications of established pharmacological therapies for Parkinson's disease, together with major contributions from animal research to elucidate the roles of the basal ganglia in movement disorders, inspired a recent renaissance in neurosurgical interventions for Parkinson's disease including deep brain stimulation; this continues to yield much neurophysiological information. The development of potentially restorative treatment modalities, such as gene therapy, neural transplantation and nanotechnology, hold much promise for surgery, both therapeutically and in revealing further insights into Parkinson's disease pathophysiology.
PMCID: PMC1457758  PMID: 16672757
15.  Neural Plasticity in Human Brain Connectivity: The Effects of Long Term Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson’s Disease 
PLoS ONE  2014;9(1):e86496.
Background
Positive clinical outcomes are now well established for deep brain stimulation, but little is known about the effects of long-term deep brain stimulation on brain structural and functional connectivity. Here, we used the rare opportunity to acquire pre- and postoperative diffusion tensor imaging in a patient undergoing deep brain stimulation in bilateral subthalamic nuclei for Parkinson’s Disease. This allowed us to analyse the differences in structural connectivity before and after deep brain stimulation. Further, a computational model of spontaneous brain activity was used to estimate the changes in functional connectivity arising from the specific changes in structural connectivity.
Results
We found significant localised structural changes as a result of long-term deep brain stimulation. These changes were found in sensory-motor, prefrontal/limbic, and olfactory brain regions which are known to be affected in Parkinson’s Disease. The nature of these changes was an increase of nodal efficiency in most areas and a decrease of nodal efficiency in the precentral sensory-motor area. Importantly, the computational model clearly shows the impact of deep brain stimulation-induced structural alterations on functional brain changes, which is to shift the neural dynamics back towards a healthy regime. The results demonstrate that deep brain stimulation in Parkinson’s Disease leads to a topological reorganisation towards healthy bifurcation of the functional networks measured in controls, which suggests a potential neural mechanism for the alleviation of symptoms.
Conclusions
The findings suggest that long-term deep brain stimulation has not only restorative effects on the structural connectivity, but also affects the functional connectivity at a global level. Overall, our results support causal changes in human neural plasticity after long-term deep brain stimulation and may help to identify the underlying mechanisms of deep brain stimulation.
doi:10.1371/journal.pone.0086496
PMCID: PMC3899266  PMID: 24466120
16.  MEG Can Map Short and Long-Term Changes in Brain Activity following Deep Brain Stimulation for Chronic Pain 
PLoS ONE  2012;7(6):e37993.
Deep brain stimulation (DBS) has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG) data from a patient with whole-body chronic pain, in order to investigate changes in neural activity induced by DBS for pain relief over both short- and long-term. This patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). We demonstrate that a novel method, null-beamforming, can be used to localise accurately brain activity despite the artefacts caused by the presence of DBS electrodes and stimulus pulses. The accuracy of our source localisation was verified by correlating the predicted DBS electrode positions with their actual positions. Using this beamforming method, we examined changes in whole-brain activity comparing pain relief achieved with deep brain stimulation (DBS ON) and compared with pain experienced with no stimulation (DBS OFF). We found significant changes in activity in pain-related regions including the pre-supplementary motor area, brainstem (periaqueductal gray) and dissociable parts of caudal and rostral ACC. In particular, when the patient reported experiencing pain, there was increased activity in different regions of ACC compared to when he experienced pain relief. We were also able to demonstrate long-term functional brain changes as a result of continuous DBS over one year, leading to specific changes in the activity in dissociable regions of caudal and rostral ACC. These results broaden our understanding of the underlying mechanisms of DBS in the human brain.
doi:10.1371/journal.pone.0037993
PMCID: PMC3366994  PMID: 22675503
17.  Impact of Emotion on Consciousness: Positive Stimuli Enhance Conscious Reportability 
PLoS ONE  2011;6(4):e18686.
Emotion and reward have been proposed to be closely linked to conscious experience, but empirical data are lacking. The anterior cingulate cortex (ACC) plays a central role in the hedonic dimension of conscious experience; thus potentially a key region in interactions between emotion and consciousness. Here we tested the impact of emotion on conscious experience, and directly investigated the role of the ACC. We used a masked paradigm that measures conscious reportability in terms of subjective confidence and objective accuracy in identifying the briefly presented stimulus in a forced-choice test. By manipulating the emotional valence (positive, neutral, negative) and the presentation time (16 ms, 32 ms, 80 ms) we measured the impact of these variables on conscious and subliminal (i.e. below threshold) processing. First, we tested normal participants using face and word stimuli. Results showed that participants were more confident and accurate when consciously seeing happy versus sad/neutral faces and words. When stimuli were presented subliminally, we found no effect of emotion. To investigate the neural basis of this impact of emotion, we recorded local field potentials (LFPs) directly in the ACC in a chronic pain patient. Behavioural findings were replicated: the patient was more confident and accurate when (consciously) seeing happy versus sad faces, while no effect was seen in subliminal trials. Mirroring behavioural findings, we found significant differences in the LFPs after around 500 ms (lasting 30 ms) in conscious trials between happy and sad faces, while no effect was found in subliminal trials. We thus demonstrate a striking impact of emotion on conscious experience, with positive emotional stimuli enhancing conscious reportability. In line with previous studies, the data indicate a key role of the ACC, but goes beyond earlier work by providing the first direct evidence of interaction between emotion and conscious experience in the human ACC.
doi:10.1371/journal.pone.0018686
PMCID: PMC3073993  PMID: 21494569

Results 1-17 (17)