Neurophysiological mechanisms of gait disturbance in advanced Parkinson's disease patients

Takakusaki, Kaoru; Takahashi, Mirai; Noguchi, Tomohiro; Chiba, Ryosuke

doi:10.1111/ncn3.12683

Cited by 15 publications

(20 citation statements)

References 125 publications

(419 reference statements)

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“…The exact mechanism of gait dysfunction in Parkinson’s disease is unknown but is associated with neurotransmitter abnormalities which cause disruptions in connections between the BG, PPN, and cerebellum 4 . DAergic cell loss measured in the SNc of P1KO rats may cause hyperactive oscillations in the CBLv associated with abnormal gait.…”

Section: Discussionmentioning

confidence: 99%

“…A pathological hallmark of Parkinson’s disease is dopamine (DA) degeneration in the substantia nigra pars compacta (SNc) and cholinergic degeneration in the pedunculopontine nucleus (PPN). 4 An early study of this model measured 50% DA depletion in the SNc when compared to healthy wild type (WT) rats and locomotor deficits beginning as early as 4 months and continuing up to 8 months of age. 5 Succeeding studies, however, presented mixed results.…”

Section: Introductionmentioning

confidence: 99%

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Cerebellar Activity in PINK1 Knockout Rats during Volitional Gait

DeAngelo

Hilliard

Chiang

et al. 2023

Preprint

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Preclinical models of Parkinson’s disease are imperative to gain insight into the neural circuits that contribute to gait dysfunction in advanced stages of the disease. The PTEN-induced putative kinase 1 (P1) knockout (KO) early onset model of Parkinson’s disease may be a useful rodent model to study the effects of neurotransmitter degeneration caused by loss of P1 function on brain activity during volitional gait. The goal of this study was to measure changes in neural activity at the cerebellar vermis (CBLv) at 8 months of age. Gait deficits, except run speed, were not significantly different from age-matched wild-type (WT) controls as previously reported. P1KO (n=4) and WT (n=4) rats were implanted with a micro-electrocorticographic array placed over CBLv lobules VI (a, b, and c) and VII. Local field potential recordings were obtained during volitional gait across a runway. Power spectral analysis and coherence analysis were used to quantify network oscillatory activity in frequency bands of interest. CBLv power was hypoactive in the beta (VIb, VIc, and VII) and alpha (VII) bands at CBLv lobules VIb, VIc, and VII in P1KO rats compared to WT controls during gait (p<0.05). These results suggest that gait improvement in P1KO rats at 8 months may be a compensatory mechanism attributed to movement corrections caused by decreased inhibition of the alpha band of CBLv lobule VII and beta band of lobules VIb, VIc, and VII. The P1KO model may be a valuable tool for understanding the circuit mechanisms underlying gait dysfunction in early-onset Parkinson’s disease patients with functional loss of P1. Future studies investigating the CBLv as a potential biomarker and therapeutic target for the treatment of gait dysfunction in Parkinson’s disease are warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cerebellar Activity in PINK1 Knockout Rats during Volitional Gait

DeAngelo

Hilliard

Chiang

et al. 2023

Preprint

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“…[28][29] Cortical activity is reduced in Parkinson's disease. 1 Hyperactivation of this lobule may be a response to impaired behavioral and motor planning due to a disconnection of the cortico-BG circuits, resulting in impaired gait. Although gait impairments were not statically significantly different at this timepoint, measures still showed deficits in the 6-OHDA rats compared to the controls.…”

Section: Cell Countingmentioning

confidence: 99%

“…Although the exact mechanism is unclear, gait deficits typically appear with substantia pars compacta (SNc) dopamine (DA) loss exceeding 40% and become pronounced after 68% loss. [1][2][3][4][5][6] Symptoms present as shuffled gait, decreased stride length, and decreased velocity. 6 FOG is the most difficult symptom to treat and is defined as the episodic absence or marked reduction of forward progression of gait despite the intention to walk.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][15][16][17][18] Cerebellar vermis (CBLv) contributions to gait dysfunction in Parkinson's disease has been linked to degeneration in the pedunculopontine nucleus (PPN) and basal ganglia (BG). 1,14,44 To our knowledge, the current understanding of CBLv changes in Parkinson's disease are limited to results from imaging studies which measure activity indirectly by coupling activity to increases in blood flow 20 and EEG recordings, which have limited spatial resolution. 19 Hanakawa et al found that the CBLv is hyperactive in Parkinson's disease patients experiencing gait dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Cerebellar Activity in Hemi-Parkinsonian Rats during Volitional Gait and Freezing

DeAngelo

Gehan

Paliwal

et al. 2023

Preprint

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Parkinson’s disease is a neurodegenerative disease characterized by gait dysfunction in the advanced stages of the disease. The unilateral 6-OHDA toxin-induced model is the most studied animal model of Parkinson’s disease, which reproduces gait dysfunction after greater than 68% dopamine (DA) loss in the substantia nigra pars compacta (SNc). The extent to which the neural activity in hemi-parkinsonian rats correlates to gait dysfunction and DAergic cell loss is not clear. In this paper we report the effects of unilateral DA depletion on cerebellar vermis activity using micro-electrocorticography (μECoG) during walking and freezing on a runway. Gait and neural activity were measured in 6-OHDA lesioned and sham lesioned rats at 14d, 21d, and 28d after infusion of 6-OHDA or control vehicle into the medial forebrain bundle (MFB) (n=20). Gait deficits in 6-OHDA rats were different from sham rats at 14d (p<0.05). Gait deficits in 6-OHDA rats improved at 21d and 28d except for run speed, which decreased at 28d (p=0.018). No differences in gait deficits were observed in sham lesioned rats at any time points. Hemiparkinsonian rats showed hyperactivity in the cerebellar vermis at 21d (p<0.05), but not at 14d and 28d, and the activity was reduced during freezing epochs in lobules VIa, VIb, and VIc (p<0.05). These results suggest that DAergic cell loss causes pathological cerebellar activity at 21d postlesion and suggests that compensatory mechanisms from the intact hemisphere contribute to normalized cerebellar activity at 28d. The decrease in cerebellar oscillatory activity during freezing may be indicative of neurological changes during freezing of gait in Parkinson’s disease patients making this region a potential location for biomarker detection. Although the unilateral 6-OHDA model presents gait deficits that parallel clinical presentations of Parkinson’s disease, further studies in animal models of bilateral DA loss are needed to understand the role of the cerebellar vermis in Parkinson’s disease.

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New Insights into Freezing of Gait in Parkinson's Disease from Spectral Dynamic Causal Modeling

Taniguchi,

Kajiyama,

Kochiyama

et al. 2024

Movement Disorders

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BackgroundFreezing of gait is one of the most disturbing motor symptoms of Parkinson's disease (PD). However, the effective connectivity between key brain hubs that are associated with the pathophysiological mechanism of freezing of gait remains elusive.ObjectiveThe aim of this study was to identify effective connectivity underlying freezing of gait.MethodsThis study applied spectral dynamic causal modeling (DCM) of resting‐state functional magnetic resonance imaging in dedicated regions of interest determined using a data‐driven approach.ResultsAbnormally increased functional connectivity between the bilateral dorsolateral prefrontal cortex (DLPFC) and the bilateral mesencephalic locomotor region (MLR) was identified in freezers compared with nonfreezers. Subsequently, spectral DCM analysis revealed that increased top‐down excitatory effective connectivity from the left DLPFC to bilateral MLR and an independent self‐inhibitory connectivity within the left DLPFC in freezers versus nonfreezers (>99% posterior probability) were inversely associated with the severity of freezing of gait. The lateralization of these effective connectivity patterns was not attributable to the initial dopaminergic deficit nor to structural changes in these regions.ConclusionsWe have identified novel effective connectivity and an independent self‐inhibitory connectivity underlying freezing of gait. Our findings imply that modulating the effective connectivity between the left DLPFC and MLR through neurostimulation or other interventions could be a target for reducing freezing of gait in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Neurophysiological mechanisms of gait disturbance in advanced Parkinson's disease patients

Cited by 15 publications

References 125 publications

Cerebellar Activity in PINK1 Knockout Rats during Volitional Gait

Cerebellar Activity in PINK1 Knockout Rats during Volitional Gait

Cerebellar Activity in Hemi-Parkinsonian Rats during Volitional Gait and Freezing

New Insights into Freezing of Gait in Parkinson's Disease from Spectral Dynamic Causal Modeling

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