A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation

Thevathasan, Wesley; Cole, Michael H.; Graepel, Cara; Hyam, Jonathan A.; Jenkinson, Ned; Brittain, John-Stuart; Coyne, Terry; Silburn, Peter A.; Aziz, Tipu Z.; Kerr, Graham; Brown, Peter

doi:10.1093/brain/aws039

Cited by 132 publications

(125 citation statements)

References 47 publications

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“…A high filter order (1000) was used to isolate narrow sub-bands of the LFP in order to distinguish, for example, high alpha oscillations (10-12 Hz) from low beta oscillations (12)(13)(14)(15)(16)(17)(18)(19)(20). The filtered signal was Hilbert transformed to extract the signal phase, and then the spike phase distribution (i.e.…”

Section: Phase Locking Of Spikes To Local Field Potentialmentioning

confidence: 99%

“…Within the MLR, the pedunculopontine nucleus (PPN), that is extensively connected with the basal ganglia 11 , has a central role in the initiation and maintenance of gait [12][13][14] and lesions of the PPN induce gait deficits 14 . Gait and postural disturbances in PD are accompanied by cell loss within the PPN [14][15][16] , but are partially relieved by deep brain stimulation (DBS) in the PPN [17][18][19] , supporting the central role of the PPN in locomotion.Much is understood about the development and function of spinal cord CPGs 20 . However, while CPG function is controlled by afferent projections from the MLR 9, 10 , little is understood about activity within the MLR, and its response to movement.…”

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confidence: 99%

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Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus

et al. 2014

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The pedunculopontine nucleus (PPN) is a part of the mesencephalic locomotor region and thought to play a key role in the initiation and maintenance of gait. Lesions of the PPN induce gait deficits, and the PPN has therefore emerged as a target for deep brain stimulation for the control of gait and postural disability. However, the role of the PPN gait control is not understood. Here, using extracellular single unit recordings in awake patients, we show that neurons in the PPN discharge as synchronous functional networks whose activity is phase locked to alpha oscillations. Neurons within the PPN respond to limb movement and imagined gait by dynamically changing network activity, and decreasing alpha phase locking. These results show that different synchronous networks are activated during initial motor planning and actual motion, and suggest that changes in gait initiation in PD may result from disrupted network activity in the PPN. IntroductionParkinson's disease (PD) is a progressive neurodegenerative disorder characterised by bradykinesia, rigidity and tremor, thought to result from loss of dopaminergic neurons 1 . Treatment of PD is symptomatic, with dopamine replacement with levodopa being the mainstay of treatment 2 . However, after an initial period of improvement, the beneficial effects of levodopa are overshadowed by side-effects such as dyskinesia and neuropsychiatric complications 3 . Moreover, in advanced PD, axial symptoms such as freezing of gait and postural difficulties become increasingly prevalent. Whereas the motor symptoms of PD are responsive to dopamine replacement, gait freezing and postural instability respond poorly. The pathophysiology of these gait disturbances is poorly understood, but their late onset and resistance to levodopa has led to the suggestion that they may result from pathology in nondopaminergic structures involved in locomotion 4,5 .Gait is controlled by genetically defined neuronal networks, the central pattern generators (CPGs), in the spinal cord 6,7 , which are in turn activated by supraspinal centres that initiate and control movement [6][7][8] . Among these, the mesencepalic locomotor region (MLR) in the brainstem plays a key role in the control of gait 9,10 . Within the MLR, the pedunculopontine nucleus (PPN), that is extensively connected with the basal ganglia 11 , has a central role in the initiation and maintenance of gait [12][13][14] and lesions of the PPN induce gait deficits 14 . Gait and postural disturbances in PD are accompanied by cell loss within the PPN [14][15][16] , but are partially relieved by deep brain stimulation (DBS) in the PPN [17][18][19] , supporting the central role of the PPN in locomotion.Much is understood about the development and function of spinal cord CPGs 20 . However, while CPG function is controlled by afferent projections from the MLR 9, 10 , little is understood about activity within the MLR, and its response to movement. In this study, using single unit recordings in awake patients, we describe the properties of neurons in t...

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Section: Phase Locking Of Spikes To Local Field Potentialmentioning

confidence: 99%

mentioning

confidence: 99%

Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus

et al. 2014

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“…C 2 : side preference during the outcome epoch for all neurons that preferred ipsilateral movement during the movement epoch. model may be useful for informing PPTg deep brain stimulation therapies for movement disorders (Benarroch 2013;Fasano et al 2012;Gradinaru et al 2009;Insola et al 2012;Khan et al 2012;Lourens et al 2011;Nandi et al 2008;Peppe et al 2010;Thevathasan et al 2010Thevathasan et al , 2011aThevathasan et al , 2011bThevathasan et al , 2012aThevathasan et al , 2012bWilcox et al 2011).…”

Section: Pptg Function Across Speciesmentioning

confidence: 99%

Activity in mouse pedunculopontine tegmental nucleus reflects action and outcome in a decision-making task

Thompson

Felsen

2013

Journal of Neurophysiology

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Recent studies across several mammalian species have revealed a distributed network of cortical and subcortical brain regions responsible for sensorimotor decision making. Many of these regions have been shown to be interconnected with the pedunculopontine tegmental nucleus (PPTg), a brain stem structure characterized by neuronal heterogeneity and thought to be involved in several cognitive and behavioral functions. However, whether this structure plays a general functional role in sensorimotor decision making is unclear. We hypothesized that, in the context of a sensorimotor task, activity in the PPTg would reflect task-related variables in a similar manner as do the cortical and subcortical regions with which it is anatomically associated. To examine this hypothesis, we recorded PPTg activity in mice performing an odor-cued spatial choice task requiring a stereotyped leftward or rightward orienting movement to obtain a reward. We studied single-neuron activity during epochs of the task related to movement preparation, execution, and outcome (i.e., whether or not the movement was rewarded). We found that a substantial proportion of neurons in the PPTg exhibited direction-selective activity during one or more of these epochs. In addition, an overlapping population of neurons reflected movement direction and reward outcome. These results suggest that the PPTg should be considered within the network of brain areas responsible for sensorimotor decision making and lay the foundation for future experiments to examine how the PPTg interacts with other regions to control sensory-guided motor output.

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“…As the electrical setup is concerned, the best clinical impact on gait in our patients has been obtained with stimuli delivered at 40 Hz, having voltage of 2-4 V and pulse width of 60 µs [32,185]. A similar setup has been also successful adopted in other studies [36,186]. In animal studies a similar frequency has been proved to be effective in inducing locomotion [181,187].…”

Section: Resultsmentioning

confidence: 99%

Participation of the pedunculopontine tegmental nucleus in arousal-demanding functions

Vitale¹,

Capozzo²,

Mazzone³

et al. 2017

Transl Brain Rhythmicity

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The pedunculopontine tegmental nucleus (PPTg) is part of the locomotor mesencephalic region and the reticular activating system (RAS). As such, it is involved in regulating some aspects of the motor control and the wake/sleep cycle, but the way in which it operates is unclear. PPTg neurons respond to a variety of sensory stimuli and to cues that trigger the execution of goal-directed motor acts. In this paper, we discuss data that suggest that in addition to operating via thalamic nuclei, the PPTg may also operate by activating cerebellar nuclei, especially the dentate nucleus. In such a way, an intense and diffuse activation of the cerebral cortex may be achieved. In arousal-demanding reward-related tasks, separate populations of PPTg neurons modulate their discharge pattern to encode, in particular, expectancy and magnitude of reward. These neuronal responses, which should reach thalamic, basal ganglia, and cerebellar nuclei through ascending PPTg fibers are essential for the formation of stimuli-reward associations and action selection. In parallel, PPTg neurons, via descending fibers directed to lower brainstem and spinal motor structures, may automatically influence motor mechanisms and muscle tone in order to cause movements that are executed in a smooth and timely manner. In patients affected by Parkinson's disease, PPTg deep brain stimulation may increase arousal, thus making patients more attentive to behavioral stimuli that trigger motor act, while simultaneously facilitating movement.

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A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation

Cited by 132 publications

References 47 publications

Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus

Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus

Activity in mouse pedunculopontine tegmental nucleus reflects action and outcome in a decision-making task

Participation of the pedunculopontine tegmental nucleus in arousal-demanding functions

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