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Title: Neural Control of Walking in People with Parkinsonism

Author block: *Peterson DS1,2, Horak FB1,2

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Affiliations:

Veterans Affairs Portland Health Care System (VAPORHCS), Portland OR

Oregon Health & Science University, Department of Neurology, Portland, OR

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*Corresponding Author

Daniel Peterson, PhD

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Oregon Health & Science University

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3181 SW Sam Jackson Park Road, OP32

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Portland, OR 97239

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503 418 2601

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petedani@ohsu.edu

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Secondary contact

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Fay Horak, PhD, PT

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Oregon Health & Science University

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3181 SW Sam Jackson Park Road, OP32

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Portland, OR 97239

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horakf@ohsu.edu

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Keywords: walking, posture, Parkinsons disease, motor control, imaging

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Words: 5552

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Summary: This review discusses the contributions of altered supraspinal locomotor

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control on gait dysfunction in people with Parkinsons disease.

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Funding

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This work was supported by grants from the United States Department of Veterans

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Affairs Rehabilitation Research and Development Service (Career Development Award1

1: #I01BX007080; PI: DP) & VA Merit Award (E1075-R; PI: FH), the National Institutes

of Health (R01 AG006457 29 PI: FH), and the Medical Research Foundation of Oregon

(Early Investigator Award; PI: DP). The contents do not represent the views of the U.S.

Department of Veterans Affairs or the United States Government.

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Financial Disclosures / Conflict of interest

Dr. Horak and OHSU have an equity/interest in APDM, a company that may have a

commercial interest in the results of the study. This potential conflict of interest has

been reviewed and managed by the Research & Development Committee at the

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Portland VA Medical Center and OHSU. No other authors declare any conflict of

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interest.

ABSTRACT

People with Parkinsons disease exhibit debilitating gait impairments, including gait

slowness, increased step variability, and poor postural control. A widespread

supraspinal locomotor network including the cortex, cerebellum, basal ganglia and

brainstem contributes to the control of human locomotion, and altered activity of these

structures underlies gait dysfunction due to Parkinsons disease.

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Abbreviations
ACh: acetylcholine
APA: anticipatory postural adjustment
MLR: mesencephalic locomotor region
nbM: nucleus basalis of Meynert
PPN: pedunculopontine nucleus
SMA: supplementary motor area

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INTRODUCTION

The ability to walk is severely impaired in people with Parkinsons disease, and these

impairments are associated with reduced quality of life, frequent falls, and complications

from falls such as increased morbidity and mortality(6, 96). Recently, a widespread

supraspinal locomotor network has been described, including pre-motor cortical, motor

cortical, basal ganglia, cerebellar, and brainstem structures(66, 137). PD impairs

structure and function in all of these locomotor regions, and these pathological and

compensatory changes contribute to Parkinsonian gait, characterized by its slowness,

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variability, and poor postural control. In this review, we first discuss the basis for these

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three primary Parkinsonian gait impairments. Then, we discuss how altered structure

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and function of supraspinal locomotor regions contribute to gait impairments in PD.

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GAIT IMPAIRMENTS IN PEOPLE WITH PD

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Gait impairments associated with PD can be broadly separated into continuous and

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transient disturbances(45). Continuous gait control problems have been recently

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characterized using principle component analysis, as consisting of five independent

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domains- pace, rhythm, variability, asymmetry, and postural control (Figure 1b,(41)). For

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the purposes of this review, we have consolidated these domains to three primary gait

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impairments: 1) gait slowness (pace, rhythm), 2) increased variability and asymmetry,

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and 3) poor postural control. These impairments have been shown to be relatively

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independent(22, 41) and we postulate each depends upon partially distinct neural

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networks. Transient gait disturbances include occasional, context-specific festination

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(rapid, short steps) and freezing of gait (either akinesia or trembling of the legs)(126). In

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the current review, we will not discuss these transient disturbances, but refer to several

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recent reviews(34, 46, 102, 103).

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Figure 1 about here

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Slowness of Gait: Gait slowness is common in people with PD(93), and can be

observed throughout the course of the disease. The primary causes of gait slowness

are: 1) hypokinesia (reduced step size)/bradykinesia (increased step duration), and 2)

rigidity/hypertonia.

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Hypokinesia and bradykinesia of gait in PD. Parkinsonian gait is both hypokinetic (e.g.

small movements such as reduced step amplitude and arm swing) and bradykinetic

(e.g. slow movements such as slower step and arm swing velocity)(22, 41). However,

reduced size of steps may be a more consistent contributor to slowed gait than slower

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steps(93). Similar to voluntary, upper extremity movement, most aspects of step

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kinematics and kinetics (e.g. joint angles, ground reaction forces, arm swing, etc.) are

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diminished in PD(92, 93). These findings suggest that in the absence of transient

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disturbances such as freezing, the primary pathology of PD gait is inadequate scaling of

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motor output rather than the coordination of locomotor patterns(27, 28, 87). One notable

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exception is the increase in co-contraction of agonists and antagonists in the shank

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during walking(30). Hypokinesia and bradykinesia of gait is also apparent in the small

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and slow arm swing and lack of axial trunk rotation in people with PD, even after

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controlling for gait speed(156). Despite hypokinetic arm swing, coordination of arm and

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leg motion is largely intact in people with PD(29).

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Rigidity/hypertonia of gait in PD. Rigidity is a specific type of hypertonicity observed in

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people with PD. Both axial and limb rigidity are observed in people with PD(84, 148),

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and both likely contribute to gait slowness. Axial tone can be measured using a device

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that slowly rotates different portions of the body, e.g. hips, trunk, and neck during quiet

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stance(48). The resistance to these slow rotations provides a measure of passive

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resistance to external movements while an individual is actively maintaining stance

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posture. This technique shows hip, trunk, and neck tone to be elevated 30-50% in

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people with PD compared to age-matched control subjects(148). Axial rigidity

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contributes to gait slowness, as hip rigidity interferes with hip hyperextension, a primary

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factor in step length and gait speed(3). Further, excessive neck tone is related to

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functional mobility, such as ability to curve gait into a figure 8 or roll over(40). Finally,
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changing gait direction with a turn is particularly slow in people with PD, even when gait

speed is normal(156). Increased trunk stiffness and resistance to twisting may

contribute to the more en block turning style of people with PD(55, 61) and the reduced

turning speed.

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People with PD also exhibit abnormal tone of the limbs including the knees and ankles.

This increased tone contributes to the flexed postural alignment of people with PD, and

contributes to gait slowness. Excessive flexor muscle actively pulls the hips, knees and

ankles into flexion, resulting in flexed spinal abnormalities, stooped posture, and

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reduced lower limb joint torques(58, 62). This abnormal posture also pushes the center

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of mass forward over the feet (125) and contributes to short, shuffling steps common in

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this population. In addition, excessive tonic muscle activity in ankle flexors and

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extensors increases co-contraction and joint stiffness(58). The elevated tone may be

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compensatory as it slows the speed and extent of body center of mass displacements

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and stabilizes joints. However increased tone and phasic antagonist co-contraction

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reduces the net joint torques for control of gait and posture. Specifically, reduction in

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net ankle plantarflexion torque, a primary propulsive force during gait, results in smaller

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steps and slower gait velocity(71). Another factor which may play a role in the reduced

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ankle plantar flexion torque, and thus reduced gait velocity, in people with PD is a

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proximal distribution of joint torques from the ankle to the hip(130).

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Increased Variability and Asymmetry of Gait. Gait variability includes stride-to-

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stride fluctuations in walking(53), and is consistently elevated in people with PD(41,

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52). Variability in the medio-lateral and anterior posterior planes may have distinct

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sources. Collins & Kuo (2013) demonstrated that step width variability, which occurs in

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the medio-lateral plane, is related to active step-to-step adjustment by the central

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nervous system to maintain balance during gait(20). This suggests that elevated lateral

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step variability observed in people with PD may partially reflect impaired control of

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lateral postural equilibrium. In contrast to medio-lateral variability, anterior-posterior

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variability of steps is closely related to fluctuations in self-selected walking speed. That

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is, anterior-posterior variability co-varies with gait speed and, in particular, the slow
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fluctuations in gait speed that are likely unrelated to step-to-step adjustments(20).

Variability of steps is larger in people with PD in both the anterior-posterior and medio-

lateral directions (52). Interestingly, increased variability of steps and reduced step

length seem to be somewhat distinct phenomenon, as increased step variability

appears prior to reduced step length, and step length is improved (increased) with

levodopa while variability is levodopa-resistant(4, 5). These results suggest the

possibility of different underlying causes for these gait measures.

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Excessive temporal and spatial left-right asymmetry of stepping parameters has also

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been consistently observed in people with PD(41, 109). For example, step length(119)

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and step time(41, 109) have been shown to be more asymmetric in people with PD than

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healthy older adults. This likely relates to the asymmetric onset of bradykinesia and

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rigidity in lower limbs as well as upper limbs. Temporal(156) and spatial(82) asymmetry

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of the arms during walking also occurs in PD. In fact, one of the earliest signs of

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abnormal gait in PD is asymmetrical arm swing amplitude(156). Even postural control

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asymmetry, measured as the velocity of center of pressure movement under the left and

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right feet during quiet stance, has been shown to be elevated in people with PD(44).

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Furthermore, gait asymmetry, along with variability, has been suggested to underlie

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more serious gait impairments, such as freezing of gait and falls(110). Thus, asymmetry

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represents an important and independent gait impairment in people with PD.

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Poor Postural Control Postural control involves maintaining, achieving, and restoring

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a state of balance during movements and posture(111). Indeed, all three components of

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postural control are impaired in people with PD and affect their gait.

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Maintaining balance during standing or walking activities requires precise control of the

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head-arms-trunk (HAT) segments(145). During standing, people with PD have

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increased area, velocity, and jerkiness of postural sway and reduced limits of stability,

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defined as the maximum center of mass displacement possible without changing ones

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base of support. Limit of stability is especially impaired in people with PD in the

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backwards direction(57) and is observed even in very early PD, prior to taking any
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antiparkinsonian medication(59, 86). In fact, the characteristic flexed, inflexible postural

alignment of people with PD results in forward position of the body center of mass,

possibly to protect against backwards falling(125). Maintenance of balance during

standing may worsen when on levodopa, possibly due to levodopa-induced

dyskinesia(18, 22). Lateral control of balance is particularly affected in people with PD,

as lateral trunk sway is especially elevated during quiet stance(1, 85) and while walking

with and without obstacles(42, 134). While some amount of lateral motion is necessary

for stability and optimized energetics(79), too much lateral motion is likely detrimental

and is related to increased falls (120).

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Achieving balance during voluntary movements such as gait initiation or fast, upper

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extremity movements is also impaired in people with PD. For example, APAs, defined

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as involuntary displacement of the center of pressure in preparation for voluntary

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movements, are bradykinetic in people with PD(86). A common example of an APA is

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the lateral and posterior movement of the center of pressure toward the swing foot prior

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to initiating a step from quiet stance. This lateral movement of the center of pressure is

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necessary to lift the stepping foot. The slow, small APAs observed in people with PD

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have been linked to delayed step initiation(76) and reduced step width, as smaller step

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widths permit smaller, lateral weight shifts during locomotion. In fact, people with PD

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have difficulty scaling up the size of their lateral APAs prior to a step when their step

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width increases, which can result in inability to take a step (akinetic freezing)(116).

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Small APAs may be due parkinsonian motor bradykineisa as slow movements require

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smaller APAs. Alternatively, APA dysfunction may be related to poor temporal coupling

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of posture (e.g. trunk lean) and gait (i.e. stepping). The coupling of posture and gait

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during walking or gait initiation is highly complex and requires precise control of the

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center of mass trajectory(83, 89, 146, 147). Unsurprisingly, people with PD have

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difficulty with posture-gait coupling (for review, see (88)), and this has been suggested

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to contribute to gait challenges including delayed step-time and freezing of gait(65).

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Interestingly, APAs can be increased to normal levels when a step is initiated in

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response to an external cue or when on levodopa(15). Recently it has been shown that
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rehabilitative interventions to assist lateral displacement of the APA may be beneficial

for improving steps in people with PD(88).

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Restoring balance after a slip, trip or other external perturbation is also dysfunctional in

people with PD. For example, people with PD exhibit smaller steps with larger

subsequent displacements of the center of mass than healthy adults in response to

large surface translations that trigger automatic compensatory stepping responses(23,

76, 131). Similarly, people with PD exhibit hypokinetic postural responses with reduced

rate of rise of reactive torque in response to smaller perturbations(58, 60). The size of

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stepping responses to external perturbations, however, can be increased when people

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with PD can see their legs as they step toward a visual target, suggesting a deficits in

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proprioception (evaluation of limb position) and/or kinesthesia (evaluation of limb

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movement)(63).

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The ability to quickly adapt postural responses based on task and environmental

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context is also altered in people with PD(16, 60). Chong and colleagues showed that if

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perturbation direction was unexpectedly altered, healthy adults immediately adapted

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their postural responses by changing postural muscle activation patterns. People with

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PD, however, took several trials before exhibiting the appropriate postural response to

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the new perturbations. This represents a relative inflexibility to alter postural responses

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to match changes in task conditions or contexts(24). However, despite potentially

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slowed rates of adaptation and learning, people with PD can eventually adapt gait and

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stepping patterns with repetition(11, 56, 90, 118).

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Summary of Gait Impairments. Slowed gait, increased variability, and poor postural

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control are the primary gait impairments in people with PD. While some gait

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impairments in people with PD are related to primary pathophysiology (such as

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bradykinesia), others may be compensatory in nature. For example, reduced step

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length and walking speed can be protective against falls as more time is spent with both

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feet on the ground at slower gait speeds. Similarly, while increased rigidity contributes

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to slowed gait(81, 99), it may also represent a compensatory mechanism to increase

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joint stiffness and joint stability. Age-related impairments in mobility (e.g. reduced

muscle strength, reduced proprioception) also reduces the ability to control the trunk or

increase walking speed. These effects are further compounded by physical inactivity

and sarcopenia that are especially pronounced in people with PD (for review, see (33)).

Therefore, while we focus our review on the possible neural underpinnings of each gait

impairment, it is important to note that compensatory mechanisms and secondary, age-

related musculoskeletal impairments also contribute to gait impairments in people with

PD, in addition to neurodegeneration.

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NEURAL UNDERPINNINGS OF GAIT DYSFUNCTION IN PD

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A definitive diagnosis of PD includes death of dopaminergic cells within the substantia

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nigra pars compacta that project to the striatum (i.e. caudate and putamen) of the basal

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ganglia. Often overlooked, however, is that numerous other brain regions also show

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altered structure and function in people with PD. For instance, areas that release

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acetylcholine (ACh), such as the pedunculopontine nucleus (PPN) and nucleus basalis

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of Meynert (nbM), and noradrenaline, such as the locus coeruleus, exhibit alpha-

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synuclein deposition very early in the disease(14). Cortical motor and non-motor

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structures show considerable deposition later in the course of the disease. Cerebellar

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function is also altered in PD(149). Indeed, every critical node in the central locomotor

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network(66) likely plays a role in PD gait dysfunction. Table 1 summarizes studies

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investigating the neural activity during gait or gait like tasks, showing reduced or

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increased activity in a number of brain regions (or nodes) within the locomotor/postural

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network in people with PD. In the following section, we will discuss how these changes

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in supraspinal activity may contribute to the gait dysfunction described above: gait

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slowness, variability/asymmetry, and impaired postural control.

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Table 1 about here

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Neural Underpinnings of Slowed Gait

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Hypokinesia and bradykinesia contribute to slowed gait, and may be explained partially

by the long- standing rate-model of basal ganglia pathology in PD(2, 26, 43). Although

this model has been adapted over time(25), it remains a commonly used model of motor

dysfunction in PD and supports a critical role of the basal ganglia in scaling self-initiated

movement.

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Figure 2 about here

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Figure 2 depicts the rate model of basal ganglia pathophysiology in people with PD.

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This model suggests that neural degeneration of the substantia nigra pars compacta

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results in increased inhibition of the globus pallidus external segment and reduced

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inhibition of the globus pallidus internal segment. Together, this leads to over-excitation

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of the globus pallidus internal segment and thus more inhibition of the thalamus and

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PPN. Interestingly, recent research suggests that increased inhibitory output from the

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pons (an area affected early in the course of PD(14), may further exacerbate these

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changes by suppressing substantia nigra output(32).

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Figure 3 about here

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These alterations in basal ganglia output result in over-inhibition of the ventral

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anterior/ventral lateral thalamus and reduced excitation of cortical motor structures such

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as the supplementary motor area (SMA) and primary motor cortex (72, 135) (Fig. 3-1).

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Given the importance of these motor and pre-motor regions for movement scaling and

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planning(97) the reduced excitation of the SMA could lead to hypokinetic gait, APAs,

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and automatic postural responses(49, 136, 139). This hypothesis is supported by the

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fact that gait and APA hypokinesia is improved by levodopa in the early stages of the

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disease. Indeed, we recently showed that hypokinesia (e.g. step length, gait velocity,

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and arm swing) was the gait impairment most improved by levodopa. These results are

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shown in Figure 4, which depicts the effects of levodopa on different gait domains (e.g.

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pace, arm and trunk movement, dynamic stability, etc.), in 104 individuals with
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idiopathic PD. Interestingly, other measures of gait dysfunction, including gait timing and

postural sway were unaffected, or even worsened, respectively, by levodopa(22).

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Figure 4 about here

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The notion that altered basal ganglia-thalamo-cortical function is related to gait

slowness is supported by recent neuroimaging studies (Table 1). For example,

Hanakawa and colleagues (1999) showed that SMA activity was reduced in people with

PD with respect to healthy adults during actual walking(51). More recent studies have

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shown that the amount of activation in the SMA during imagined walking was correlated

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to overground gait function in people with PD(21, 105). In addition, basal ganglia

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activity(105) and the availability of dopamine in the nigrostriatal system(104) are

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reduced in people with PD during locomotion with respect to healthy adults.

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Dysfunction of locomotor network regions outside of the basal ganglia-thalamo-cortical

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system, including areas related to cholinergic activity, have also been implicated in gait

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slowness in people with PD. ACh in the brain comes from three primary sources:

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cholinergic interneurons in the striatum; the nbM, which is the primary source of ACh to

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the cortex and basal forebrain, and the PPN, which supplies cholinergic input to the

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thalamus and spinal cord (for review, see(154)). Recent work suggests that the

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availability of cortical ACh, supplied by the nbM, may be specifically related to gait

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speed. For example, among a cohort of 125 people with PD, gait speed was not

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affected in people with PD with nigrostriatal denervation and normal cholinergic

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denervation. In contrast, gait speed was significantly reduced in individuals with both

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nigrostriatal and cholinergic denervation. This suggests that gait speed may be related to

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either cholinergic dysfunction (alone) or in conjunction with dopaminergic

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dysfunction(7). Further, Rochester et al. (2012) measured cortical cholinergic availability

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using transcranial magnetic stimulation, showing correlations between gait speed and

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step length with cortical cholinergic function(117). These findings suggest that impaired

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cortical ACh dysfunction (supplied primarily by the nbM), together with dopamine

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dysfunction may lead to reduced gait speed. Indeed, although the substantia nigra is
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commonly noted as the source of motor dysfunction in PD, the nbM is among the first

structures to exhibit structural pathology in the course of PD(14). In addition to the nbM,

the PPN may also play a role in hypokinesia, as PPN lesions in primates cause arm and

leg hypokinesia(77, 95). Interestingly, The PPN may also play a role in akinesia, or the

lack of movement. Jenkinson and colleagues showed that levodopa in combination with

PPN stimulation improved the mean number of movements per hour in a parkinsonian

primate to normal levels(69), again suggesting that both dopaminergic and non-

dopaminergic dysfunction are critical for movement production.

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In contrast to reduced activity of cortical and brainstem areas, several investigations

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have shown increased activity in the cerebellum, possibly compensating for altered

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basal ganglia function. This compensatory hypothesis has been supported by several

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recent investigations (for review see (149)). A single proton emission computed

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tomography study during locomotion showed concomitant increased activity in midline

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cerebellum and decreased activity of the SMA in people with PD(51). In a follow-up

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study, Hanakawa and colleagues showed that while walking with transverse lines on the

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floor (visual cues) gait in people with PD was improved and the cerebellum and lateral

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premotor cortex were especially active. The premotor cortex, which is partially regulated

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by the cerebellum, is related to externally cued movement(122). In contrast, the SMA,

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which receives considerable input from the basal ganglia, may preferentially contribute

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to internally driven movement(97). Therefore, in people with PD the cerebellum may

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regulate gait using external cues, compensating for poorer internally generated

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movement via the basal ganglia and SMA(50). More recently, Festini and colleagues

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demonstrated that when OFF anti-Parkinson medication (levodopa), people with PD

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exhibit increased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity.

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Further, increased cerebellar activity was, in some cases, correlated to improved motor

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and cognitive performance in PD(35). The cerebellum plays a critical role in the

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generation(112) and timing(31) of movements, particularly during locomotion(67, 91),

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and is densely connected with the locomotor brainstem areas (such as PPN)(68), the

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basal ganglia(12, 13), and the cortex. Further, this region has recently been shown to

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exhibit relatively high presynaptic cholinergic terminals, underscoring its importance

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within the cholinergic system(107). Thus, although the mechanism is not fully

understood, increased activity of the cerebellum in PD may be an attempt to

compensate for reduced activity of other structures, including the SMA, but may result in

overdependence on external cues(8, 51, 149) (Fig 3-2).

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Hypertonicity/rigidity in PD likely results from impaired basal ganglia control of postural

regions within the brainstem(80) (Fig. 3-4). Despite their congruent role in gait

slowness, hypokinesia/bradykinesia and rigidity may have somewhat distinct neural

underpinnings(70). While hypo and bradykinesia are related primarily to dysfunction of

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the cortico-thalamo-basal ganglia loop (see previous section), rigidity may be related to

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dysfunction of the interaction between the basal ganglia and deep brain structures

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including the cholinergic, region of the PPN. Converging animal and human

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experiments suggest that the PPN and MLR within the brainstem play critical roles for

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controlling axial postural tone. Specifically, the MLR, consisting primarily of the

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cuneiform nucleus, contributes to the muscle tone excitatory and rhythm generating

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system(137). In animals, tonic activity of this region can elicit gait-like flexion and

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extension of hindlimbs. Conversely, the PPN inhibits extensor and flexor alpha motor

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neurons(138). Both the MLR and PPN receive considerable efferent, inhibitory signals

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from the GPi(137) and, as noted above, people with PD exhibit excessive inhibitory

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output from the GPi. Thus the elevated inhibition of the MLR in PD likely reduces the

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ability to initiate and maintain locomotion. In contrast, inhibition of the inhibitory system

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(i.e. the PPN), may result in hypertonus and rigidity(140). However, axial and limb

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rigidity are somewhat distinct, due to the different pathways from dorsolateral (axial) and

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ventromedial (limbs) descending spinal systems(80). In fact, although levodopa is very

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effective in reducing limb rigidity(58), it does not reduce axial rigidity(40, 148). Thus,

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primary dysfunction of the PPN, either prior to, or secondary to, nigrostriatal dysfunction

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may contribute to increased axial tone.

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Neural Underpinnings of Variability and Asymmetry in PD Gait

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Gait variability and asymmetry in people with PD has been well characterized; however

the neural underpinnings of this impairment are not well understood. One hypothesis

suggests that people with PD have difficulty controlling automatic movements, and thus

shift to more voluntary control of gait(8). This compensatory shift from automatic gait to

voluntary stepping may result in more gait variability(19, 153) (Fig. 3-5). Indeed,

considerable research has shown that conscious control of typically overlearned tasks

reduces performance and increases variability(153). Automatic tasks seem to rely more

on subcortical structures, including the basal ganglia and brainstem, whereas voluntary

tasks rely more on cortical activity, and require more attention(19, 49, 140, 151, 152).

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People with PD exhibit larger than normal cortical activity during upper extremity motor

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tasks, both when the task is new and after overlearning has occurred(150, 152),

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suggesting more voluntary control of tasks in this population. Thus, even highly

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overlearned tasks, such as walking, may rely more heavily on cortical structures in PD.

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This shift toward increased voluntary locomotor control may partially compensate for

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dysfunction of the basal ganglia and brainstem automatic pathways, however may also

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increase variability.

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Dual task paradigms provide further support of PD impairments in automatic control of

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gait leading to increased variability while walking(74). When completing gait with a

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secondary cognitive task, healthy adults typically demonstrate decrements in both the

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cognitive task (e.g. counting backwards by 3s) and gait. These decrements in

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performance are noted as dual task cost. Because cognitive tasks are primarily

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supported by frontal structures and require attention, dual task cost suggests that the

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primary, motor task (e.g. walking) also requires a level of attention and voluntary

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control. Interestingly, people with PD have more pronounced dual task cost during

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walking than age-matched adults(74). This increased dual task cost in people with PD

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suggests that gait requires more attentional, voluntary control than in healthy adults,

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resulting in increased variability(106, 108).

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Gait asymmetry may be related directly to asymmetric neural dysfunction within the

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basal ganglia. Dopaminergic neuron loss is often asymmetric, and the side with greater
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dopamine loss corresponds to the opposite side with greater motor signs in humans(75,

78, 114, 141), and in animals(39). Similarly, asymmetry of rigidity and bradykinesia

have been shown to relate to asymmetric limb movements during gait, asymmetric

turning impairments and asymmetric dopaminergic degeneration(144). Finally, a recent

report suggests increased levodopa use may improve asymmetry of gait(41).

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Neural Underpinnings of Poor Postural Control in PD Gait

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Considerable research is pointing toward an important role of non-dopaminergic

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structures such as the PPN in postural dysfunction of people with PD (Fig. 3-4). For

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example, trunk sway and variability in the mediolateral direction, common measures of

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postural control, are excessive in people with PD; but do not correlate well with other

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PD signs, such as the UPDRS(85), and are not consistently improved by levodopa(113,

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115). In fact, lateral sway during stance may be increased after taking levodopa;

15

possibly due to reduced rigidity, with no concomitant improvement in postural

16

control(116). Muller and colleagues recently demonstrated that thalamic cholinergic

17

innervation, i.e. the amount of cholinergic neurons projecting from the PPN to the

18

thalamus, was directly correlated to postural sway(94). Importantly, no correlations were

19

observed between postural sway and cortical ACh innervation. In contrast, Rochester

20

and colleagues showed that gait speed, but not step width variability (a measure of

21

postural control) was related to cortical ACh activity(117). Therefore, ACh in the

22

thalamus, supplied primarily by the PPN, seems to be related to postural control (e.g.

23

postural sway and sway variability)(94), whereas cortical cholinergic function, supplied

24

by the nbM, may be related to gait speed and hypokinesia(7, 36).

25
26

Restoring balance after an external perturbation relies on cortical, basal ganglia, and

27

brainstem structures(64). Like voluntary stepping, the hypokinetic steps in response to

28

large, external perturbations may reflect altered basal ganglia-thalamo-cortical circuitry.

29

However, levodopa does not improve compensatory stepping as it improves voluntary

30

stepping, suggesting that brain regions outside of the basal ganglia, such as areas

31

related to ACh contribute to reactive postural control strategies(23, 76). Indeed, recent
16

animal and human research suggests that automatic postural responses are stored in

the brainstem (54, 100, 101, 133). Further, ACh in the thalamus (provided primarily by

the PPN) is correlated with falls in people with PD, while dopaminergic function is

not(9). In addition, medication that improves ACh availability (donepezil and

rivostigmine) may reduce falls in people with PD(17). Together, these results suggest

that non-dopaminergic regions, including the brainstem, likely play a critical role for

postural responses and fall prevention.

8
9

Several other converging lines of evidence support the role of PPN and ACh in postural

10

control. Karachi, et al. recently showed that PPN cholinergic lesions, both with and

11

without concomitant nigrostriatal dopaminergic losses resulted in postural instability in

12

rhesus monkeys(73). Further, patients with progressive supranuclear palsy show severe

13

balance impairments and postural instability, specifically with spontaneous backward

14

falls. Progressive supranuclear palsy is an atypical parkinsonian syndrome marked by

15

PPN and thalamic cholinergic dysfunction and cell loss, but relatively spared cortical

16

cholinergic innervation(47, 129). Falls, a prominent outcome of postural instability, are

17

correlated to cholinergic innervation from the PPN to the thalamus in people with PD.

18

Bohnen & colleagues showed that fallers had reduced thalamic cholinergic function with

19

respect to non-fallers, with no similar loss in nigrostriatal dopaminergic denervation (9,

20

10). Further, a recent imaging study showed that people with PD exhibited altered PPN

21

activity during imagined walking with respect to healthy controls, providing a direct link

22

between PPN activity and gait dysfunction in people with PD(21). Deep brain structures

23

with dense connections to the PPN including the pontomedulary reticular formation

24

have also been linked to generation of APAs and coupling of posture and gait(123). For

25

example, recent electrophysiological studies in cats have shown that the pontomedulary

26

reticular formation contributes to coupling of anticipatory postural adjustments and limb

27

movements(123, 124). While the neural underpinnings of poor postural and locomotor

28

coupling in PD is not well understood, people with PD exhibit early pathology in deep

29

brain structures such as the pontomedulary reticular formation(14). Therefore, it is

30

possible that this pathology contributes to the poor coupling of posture and locomotion.

31
17

Interestingly, deep brain stimulation in the STN(98, 115) or GPi(115) has been shown to

improve some measures of postural sway in PD, including mediolateral sway velocity.

Given the intractability of postural sway to levodopa, these finding suggests that deep

brain stimulation of the STN and GPi may influence non-dopaminergic pathways.

Indeed, considerable bidirectional pathways between the STN and deep brain

structures, such as the PPN, exist, and impaired signaling from the STN to the PPN has

been suggested to be central to some postural control dysfunction in PD(128). In fact, a

recent report by Weiss and colleagues demonstrated that STN deep brain stimulation

may improve walking via direct activation of the PPN(143), further underscoring the

10

importance of both the STN and PPN in postural control in people with PD.

11
12

Together, these reports underscore the role of structures both within and outside the

13

basal ganglia including the PPN, thalamus, and cerebellum in gait dysfunction in PD.

14

Specifically, the deep brain structures and their dense connections with the cortex,

15

cerebellum, STN, and spinal cord contribute to gait dysfunction observed in people with

16

PD(37, 38).

17
18
19

CONCLUSIONS AND FUTURE DIRECTIONS

20
21

Gait impairments in people with PD include pronounced slowness, variability, and

22

postural instability. Considerable work is unraveling the pathophysiology underlying

23

these characteristics, demonstrating likely contributions from a number of supraspinal

24

regions. Specifically, slowness of gait seems to be related to dysfunction of the basal

25

ganglia-thalamo-cortical loop in conjunction with reduced cortical ACh, as well as

26

rigidity. Gait variability may be related to a shift from automatic to voluntary control of

27

locomotion in people with PD. Finally, postural instability seems to be related to

28

alterations in ACh in brain-stem structures such as the PPN and MLR. In addition to

29

these changes, increased activation in the cerebellum and cortex may partially

30

compensate for impaired activity in other brain regions, but may result in

31

overdependence on external cues.

18

1
2

Additional work is necessary to continue to elucidate mechanisms for gait dysfunction in

people with PD. Continued investigation of neural activity during actual and imagined

locomotion (for review, see:(8)), as well as structural and functional neural connectivity

will provide further insight into how the brain is differently active in people with PD who

have specific parkinsonian impairments such as freezing of gait, dyskinesia and

dystonia. Finally, new studies are focusing on the role of cognitive impairments in gait

dysfunction(127). Impairments of gait and cognition may share neural underpinnings in

the prefrontal cortex. For example, availability of cortical acetylcholine may underlie

10

attention and executive cognitive dysfunction in people with PD(154) so new trials are

11

examining the effects of cholinesterase inhibitors at improving both cognitive and gait

12

function in people with PD (121). Indeed, each of the gait characteristics discussed

13

above (slowness, variability, and postural control), have been directly linked to cognitive

14

declines, perhaps because of shared prefrontal circuitry(for review see: (155)). Further

15

work is necessary to understand how cognitive function contributes to control of

16

locomotion and gait impairments in PD.

19

Figure Legends:

2
3

Figure 1: A) Continuous gait disturbances in people with PD; B) People with PD exhibit

dysfunction in gait speed (pace/rhythm), variability and asymmetry, and postural control.

This is depicted by a satellite plot showing deviations from control subjects (dotted line).

Abbreviations: SV, step velocity; SL, step length; Swi, swing time; ST, Step time; Sta,

Stance time; Wid, Step width; sd, standard deviation (gait variability); as, asymmetry. *

indicates differences between the control and PD group. Figure reproduced with

permission from Galna et al. Mov Dis. Vol.30 No.3, 2015.

10

20

1
2

Figure 2. Rate model of basal ganglia dysfunction in normal (A), and parkinsonian (B)

states. Over activity of the indirect, and underactivity of the direct pathways result in

more inhibitory output form the basal ganglia output structures (GPi) to the thalamus

and brainstem, and ultimately reduced amplitude of movements, including gait. Green

arrows represent excitatory and red arrows represent inhibitory projections. Arrow

thickness represents the relative firing rate of projections, and dashed arrows indicate

the relative reduction of the SNpc D1 and D2 dopaminergic projections to the striatum.

Abbreviations: SNpc: substantia nigra pars reticulate; GPe: globus pallidus external

10

segment; GPi: globas pallidus internal segment; STN: subthalamic nucleus.

11

21

1
2

Figure 3. Framework for supraspinal control of locomotion in people with PD. Alterations

in activity of the basal ganglia (1) and brainstem (4) contribute to gait slowness and

increased postural instability, respectively, and increased cerebellar activity may

partially compensate for these alterations (2). Increased volitional control (i.e. cortico-

spinal) and reduced automatic control (3) may contribute to increased gait variability

and asymmetry. See text box above for more information. Abbreviations: PPN:

pedunculopontine nucleus; MLR: mesencelphalic locomotor region; PMRF:

pontomedulary reticular formation; SMA: supplementary motor area.

10
11

22

1
2

Figure 4: The dysfunction in speed, variability & asymmetry, and postural control in PD

are differently affected by levodopa. Rightward (positive) values represent a positive

impact of levodopa, while leftward (negative) values represent a negative impact of

levodopa. Gait speed and size of limb movements are improved by levodopa (top of the

figure). Postural sway can be worsened by levodopa (bottom of figure). Although few

variability or asymmetry variables were available in this particular analysis, asymmetry

of arm swing and temporal coordination, such as double support time were not

consistently improved by levodopa. A value larger than 0.20 represents small, 0.50

10

moderate, and 0.80 large responsiveness. * indicates differences between the control

11

and PD group. Reproduced with permission from Curtze et al. Mov Disord. 2015

12

Sep;30(10):1361-70.
23

Table 1. Summary of recent imagining studies showing increased or decreased activity

of supraspinal locomotor nodes during actual or imagined locomotion in people with

Parkinsons disease.

Motor

Cortical

Basal
Ganglia
Brainstem
Cerebellum

Reduction of activity in PD
SMA (L)
Dorsal Premotor (R)
M1
Precuneus (L)
Precuneus (R)
Parieto-Occipital Region
Posterior Hippocampus (L)
Superior Parietal Lobule (R)
Anterior Cingulate Cortex (R)
Anterior Cingulate Cortex (L)
Inferior Parietal Lobule (R)
Occipital
Lingual Gyri
Globus Pallidus (R)
Putamen (R,L)
PPN/MLR
Cerebral hemisphere (L)
Cerebellar Locomotor Region

References
(51)
(142)
(142)
(21, 51)
(21, 51, 142)
(21, 142)
(21)
(21, 132)
(21, 132)
(21)
(142)
(142)
(21)
(105)
(104)
(21)
(21, 51)
(21)

Increase in activity in PD

References

Temporal Cortex (R)

Insula (R)
Superior Frontal Gyrus (L)
Cingulate Cortex (L)

(51)
(51)
(51)
(51)

Cerebellar Locomotor Region

(51)

24

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