Dopamine depletion impairs gait automaticity by altering cortico-striatal and cerebellar processing in Parkinson's disease

Abstract

Impairments in motor automaticity cause patients with Parkinson's disease to rely on attentional resources during gait, resulting in greater motor variability and a higher risk of falls. Although dopaminergic circuitry is known to play an important role in motor automaticity, little evidence exists on the neural mechanisms underlying the breakdown of locomotor automaticity in Parkinson's disease. This impedes clinical management and is in great part due to mobility restrictions that accompany the neuroimaging of gait. This study therefore utilized a virtual reality gait paradigm in conjunction with functional MRI to investigate the role of dopaminergic medication on lower limb motor automaticity in 23 patients with Parkinson's disease that were measured both on and off dopaminergic medication. Participants either operated foot pedals to navigate a corridor ('walk' condition) or watched the screen while a researcher operated the paradigm from outside the scanner ('watch' condition), a setting that controlled for the non-motor aspects of the task. Step time variability during walk was used as a surrogate measure for motor automaticity (where higher variability equates to reduced automaticity), and patients demonstrated a predicted increase in step time variability during the dopaminergic "off" state. During the "off" state, subjects showed an increased blood oxygen level-dependent response in the bilateral orbitofrontal cortices (walk>watch). To estimate step time variability, a parametric modulator was designed that allowed for the examination of brain regions associated with periods of decreased automaticity. This analysis showed that patients on dopaminergic medication recruited the cerebellum during periods of increasing variability, whereas patients off medication instead relied upon cortical regions implicated in cognitive control. Finally, a task-based functional connectivity analysis was conducted to examine the manner in which dopamine modulates large-scale network interactions during gait. A main effect of medication was found for functional connectivity within an attentional motor network and a significant condition by medication interaction for functional connectivity was found within the striatum. Furthermore, functional connectivity within the striatum correlated strongly with increasing step time variability during walk in the off state (r=0.616, p=0.002), but not in the on state (r=-0.233, p=0.284). Post-hoc analyses revealed that functional connectivity in the dopamine depleted state within an orbitofrontal-striatal limbic circuit was correlated with worse step time variability (r=0.653, p<0.001). Overall, this study demonstrates that dopamine ameliorates gait automaticity in Parkinson's disease by altering striatal, limbic and cerebellar processing, thereby informing future therapeutic avenues for gait and falls prevention.

Brain lesions affecting gait recovery in stroke patients

“…Taken together, previous studies and our results show that the striatum has an important role in gait recovery. The pathway among the pedunculopontine nucleus, cerebellum, and the striatum, the supplementary motor area, and the premotor cortex contributes to gait initiation and the modulation of locomotor rhythm and postural muscle tone during locomotion (Gilat et al., ; Peterson et al., ; Takakusaki, ). Thus, injury to the caudate nucleus and putamen is important in gait recovery in stroke patients, especially in the chronic phase(Jenkinson et al., ; Takakusaki, ).…”

“…Another recent study failed to reveal specific lesion locations with regard to balance and gait function (Moon, Pyun, Tae, & Kwon, ). Previous researches for Parkinson's disease, s dorsal striatum has been known as a gait pattern generator (Gilat et al., ; Peterson, Pickett, Duncan, Perlmutter, & Earhart, ; Snijders et al., ). However, the role of dorsal striatum for gait recovery is still uncovered in stroke.…”

Convergence of fMRI and ERP measures of emotional face processing in combat‐exposed U. S. military veterans

“…In line with prior work (e.g., Cuthbert et al, 2000;Foti et al, 2009;MacNamara, Foti, & Hajcak, 2009), the LPP was evident by 500 ms after stimulus onset at centropartial recording sites. 1 A 2-mm or higher cutoff for movement is widely used in the literature for task-based fMRI (e.g., Duval et al, 2017;Epstein et al, 2007;Gilat et al, 2017;Kim et al, 2013;MacNamara et al, 2015;Rabinak et al, 2014), especially with clinical samples, who may show more movement and are more difficult to recruit. Nonetheless, different types of data (e.g., resting state) may require more stringent parameters because, unlike task-based fMRI, motion artifacts are not suppressed by averaging (Caballero-Gaudes & Reynolds, 2017).…”

“… 1 A 2mm or higher cutoff for movement is widely used in the literature for task-based fMRI (e.g., Duval et al, 2017; Epstein et al, 2007; Gilat et al, 2017; Kim et al, 2013; MacNamara, Rabinak, et al, 2015; Rabinak et al, 2014), especially with clinical samples, who may show more movement and are more difficult to recruit. Nonetheless, different types of data (e.g., resting state) may require more stringent parameters, because unlike task-based fMRI, motion artifacts are not suppressed by averaging.…”

The Neural Signature of Impaired Dual‐Tasking in Idiopathic Rapid Eye Movement Sleep Behavior Disorder Patients

“…These regions were selected based on previous work that has investigated a similar virtual gait task and related step time variability in healthy older adults and people with PD. 24,25 Cortical 8-mm spheres and subcortical 2-mm spheres were centered on MNI coordinates from these previous studies.…”