Cholinergic system changes in levodopa-unresponsive freezing of gait and failure of goal-directed motor behavior in Parkinson's disease.
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Brain cholinergic systems changes are implicated in the pathophysiology of postural instability and gait difficulties in Parkinson's disease. The presence of postural instability and gait difficulties is associated with cholinergic terminal deficits or downregulation of cholinergic neurotransmission. Preservation or upregulation of cholinergic neurotransmission may mitigate other Parkinson's disease-associated deficits to prevent postural instability and gait difficulties that are dependent on effective sensorimotor, cognitive, and emotional integration functions. Emerging evidence also suggests that dopaminergic neurotransmission is up- and downregulated in extra-striatal regions. This expanded view of complex whole brain up and downregulatory cholinergic and dopaminergic interactive processes requires a re-appraisal of pathophysiologic changes underlying mobility disturbances in Parkinson's disease. The goal of this review is to propose a novel expanded heuristic model of dynamic cholinergic and dopaminergic systems changes underlying habitual and goal-directed motor behaviors in Parkinson's disease. We hypothesize a hierarchical topographic whole-brain model where variable combinations of up- and down-regulation of cholinergic and dopaminergic neurotransmission differentially explain habitual and goal-directed motor behavior abnormalities underlying axial motor impairments. We propose that levodopa-unresponsive freezing of gait is the culmination of combined cholinergic and dopaminergic losses in selective thalamic, (para-) limbic, thalamic complex, upper tectum, upper tegmental (especially periaqueductal gray), and cerebellar brain regions. This model is based on a comparison of literature findings of cholinergic topographic deficits underlying postural instability and gait difficulties motor findings, complemented by emerging and preliminary evidence of extra-striatal dopaminergic system changes across the spectrum of Parkinson's disease. In contrast, different topographic cholinergic system deficits, associated with freezing of gait, such as the mesencephalic and cerebellar locomotor regions, diffuse striatal, and peri-central cortices - that are key pathways of dopaminergic-dependent habitual motor behaviors - are seen with levodopa-responsive but not with unresponsive freezing of gait. Cholinergic upper tegmental, including periaqueductal gray, and limbic deficits associated with levodopa-unresponsive freezing of gait also plays a role in emotional regulation. Failure of this circuitry may lead to a context-dependent downward spiral of fear of falling, which in turn compromises the motivation to move and worsens or triggers levodopa-unresponsive freezing of gait. Cholinergic losses in the periaqueductal gray upper tegmental region may acutely block goal-directed motor behavior, contributing to the panic disorder subtype of freezing of gait. Such a freezing of gait subtype may be a naturally protective defense mechanism that, in the context of the high inherent risk of freezing of gait-associated falling, becomes counterproductive. Future research should test this heuristic model.