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Advances in Therapeutic Options for Gait and Balance in Parkinson’s Disease


Locomotor and Postural Control Centers Bipedal locomotion in humans is a complex sensorimotor task requiring dynamic interaction between spinal locomotor pattern generators and hierarchically organized supraspinal locomotion centers in the brainstem, cerebellum, and forebrain. The cerebral networks are believed to modulate locomotion (e.g. gait initiation, termination, velocity, direction, and spatial orientation) and to control balance and gait by integration of multisensory information.24


Our knowledge of the hierarchical network of supraspinal locomotion centers is derived largely from basic science studies in cats, an animal with quadrupedal locomotion.25,26


While it is likely that the anatomic


systems for gait and balance are conserved in mammals, the important details of interconnectivity and physiologic regulation are likely to differ significantly. The most important regions are the cerebellar locomotor region, the mesencephalic locomotor region, and the subthalamic locomotor region. The basal ganglia, including the striatum, pallidum, subthalamic nucleus (STN), and substantia nigra, are involved in a number of parallel, functionally segregated cortical–subcortical circuits.27 These circuits support a wide range of sensorimotor, cognitive, and emotional–motivational brain functions. A main role of the basal ganglia is learning and selection of the most appropriate motor or behavioral programs.28


Dopaminergic signaling within the basal ganglia


is clearly involved in reward-based learning and action selection.29 Normal dopaminergic function is probably particularly important for establishment, selection, and sequencing of habitual patterns of action.30


Effective integration of sensory information about the visuospatial environment, body, and limb position is essential for postural control. Standing posture, for example, is affected by perturbations of visual, vestibular, and proprioceptive sensory systems.31–33


The specific role of


the basal ganglia in postural control is complex and only beginning to be unraveled, but it is believed to be involved in several functions, including:


• sensory channel integration; •





selection of automatic postural reactions generated in response to motor and sensory perturbations, such as moving visual environments;


motor control flexibility and adaptability: for example, appropriate corrective postural reactions generated in an attempt to prevent a fall are dependent upon the characteristics of the perturbation and environmental changes;


• •


regulation of muscle tone; and


modulation of the impact of cognitive factors on balance and gait, such as attention, multitasking, and knowledge or expectation of a potential perturbation, or fear of falling.34


Figure 1 provides a schematic overview of the main locomotor and postural control centers in the brain.


Parkinsonian Gait and Deficits in Central Motor Control


PD affects complex gait activities such as gait initiation, braking, and turning. These are gait elements that require the execution of coordinated sequential and/or simultaneous motor programs essential to maintain equilibrium and to generate new movements. Healthy controls are able to harmoniously perform such complex motor tasks, but PD patients exhibit impairment of these functions, resulting in freezing, postural instability, and falls.8,9,35,36


PD patients have difficulty stopping and US NEUROLOGY


* Originates from the locus ceruleus (LC). ACh = acetylcholine; CAUD = caudate nucleus; CEREB = cerebellum; CLR = cerebellar locomotor region; DA = dopamine; DLPFC = dorsolateral prefrontal cortex; GP = globus pallidus; MLR = mesencephalic locomotor region; NBM = nucleus basalis of Meynert; NE = norepinephrine; PMC = primary motor cortex; PPN = pedunculopontine nucleus; PROP = proprioception; PUT = putamen; SLR = subthalamic locomotor region; SMA = supplementary motor area; SN = substantia nigra; THAL = thalamus; VEST = vestibular; VIS = vision; VOR = vestibulo-ocular reflex; VTA = ventral tegmental area.


turning, especially when in confined spaces.7 Freezing of gait, usually


manifested as abrupt cessation of leg movement during walking, is a common cause of falls. Sudden freezes may be related to altered cortical regulation of movement execution together with progressive impairment of mesencephalic locomotor center function (see below).37


In patients with early PD, loss of dopamine is predominantly in the posterior putamen, whereas the anterioventral striatum is relatively spared.38


However, the caudate nucleus, which has a more prominent role in striatocortical cognitive functions,27


becomes more involved with


advancing PD. Striatofrontal pathways have been implicated as playing a compensatory role in gait control in patients with PD. For example, a brain positron emission tomography study found that gait activity in normal elderly people was associated with a significant decrease in dopamine activity in the putamen, with patients with PD demonstrating a more prominent decrease in the caudate nucleus and frontal cortex.39 Abnormal caudate nucleus function has been implicated in patients with PD and freezing of gait, suggesting failure of the compensatory striatofrontal pathway functions as a possible mechanism.40


Gait in PD during a freezing episode can be improved by simple sensory cues, such as visual (guiding stripes on the floor) or auditory cues.41–45


One


interpretation of the beneficial impact of appropriate sensory cueing is that dopamine-depleted basal ganglia are unable to integrate internal/external cues critical to gait and balance. Simple sensory cueing enhances cue salience. An alternative explanation is that accurate external cues facilitate focusing of attentional resources on balance/gait during complex or simultaneous tasks and enable accurate visuospatial orientation.


101


C A U D


PUT GP SLR NBM VEST VOR THAL


SN VTA


CLR


PPN/ MLR


L C


CEREB VIS


Figure 1: Schematic of the Sensory Systems, Locomotor Regions, Cortical and Subcortical Regions, and Neurochemical Projections Involved in the Regulation of Balance and Gait


DLPFC DA NE PROP SMA/PMC ACh


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