The Aging Brain & the Dorsal Basal Ganglia: Implications for Age-Related Limitations of Mobility

Abstract

The capacity to move is essential for independence and declines with age. Limitations in mobility impact ~35% of adults over 70 and the majority of adults over 85. These limitations are highly associated with disability, dependency, and survival. More than 25-years ago the term "sarcopenia" was coined to highlight the age-related loss of muscle mass and strength with the assumption being that sarcopenia led to limitations in mobility. However, contrary to expectations, recent findings clearly indicate these variables only modestly explain limitations in mobility. One likely reason the current sarcopenia variables of muscle mass and strength do not discriminate, or predict, mobility limitations well is because they are heavily influenced by musculoskeletal mechanisms and do not incorporate measures reflective of the central neural control of mobility. Unfortunately, the precise central neural changes associated with aging that lead to decreased mobility are poorly understood. This knowledge gap has hampered the development of effective interventions for mobility limitations and the subsequent reduction of major functional disability for older adults. Here, we discuss the potential role of the motor control circuit of the dorsal basal ganglia as well as dopaminergic function in age-related reductions in mobility.

Keywords: dopamine; dynapenia; gait; motor control; neural control; sarcopenia.

Figure 1.. Predicted Median Life Expectancy by Age and Gait Speed.

Reproduced with permission from Studenski et al., J Am Med Assoc, 2011 [1].

Figure 2.. (A) The Four Square Step Test (4SST) is primarily a test of motor function as it heavily challenges motor planning and initiation as well as motor sequencing and recall.

The subjects started in square 1, facing forward. The subject steps laterally into square 2, backwards to square 3, laterally to square 4, forward to square 1, backwards to square 4, laterally to square 3, forward to square 2, and laterally to square 1. (B) The 4SST is highly associated with mobility in older adults. Unpublished data from BC Clark [21].

Figure 3.. A schematic representation of the cortico-basal ganglia-thalamic circuit in mammals.

Pathway i: corticofugal projection neurons from motor areas of cortex projecting both to brainstem and spinal cord targets. These same neurons elaborate extensive collaterals in the dorsal striatum. The dorsal basal ganglia is composed of a primary input structure, striatum, which contains two opponent populations of projection neurons (schematized in blue and red) that together provide an opponent projection onto the major output nuclei, substantia nigra pars reticulate (SNr) and internal globus pallidus (GPi) (purple). In addition, the dramatic reduction in projection neuron number from cortex to striatum to SNr is indicated by the decreasing size of the schematic representations. Finally, SNr output both projects feed-forward onto premotor neurons in the pontine nuclei and superior colliculus schematized by pathway ii as well as projecting recurrently to anterior thalamic nuclei (i.e., ventrolateral, ventromedial) that project back to cortex and striatum. Dudman and Krakauer have postulated that overt movement kinematics (pathway iii) result from the combination of motor command signals (pathway i) and reward processing control signals (pathway ii). Reproduced with permission from Dudman & Krakauer, Curr Opin Neurobiol, 2016 [28].

Figure 4.. Dopamine is required for the neural representation and control of “movement vigor”. Movement vigor, a term that has largely arisen from the field of neuroeconomics, does not have a universally accepted definition per se, but is commonly used in the context of describing elementary, stimulus-driven movements, such as saccades and reaching. Within this context the operational definition is typically the inverse of the time from stimulus onset to movement completion, conditioned on distance [40,56]. This definition is based on the empirical observation that both reaction time and movement duration are influenced by the subjective value of the reward at the destination [,,–50,57,58].

Panigrahi et al. reported that: (1) a mouse model of Parkinson’s disease produces a persistent reduction in effort; (2) the neural representation of movement vigor in striatum requires dopamine; (3) and acute suppression of striatal activity during execution enervates movement; and (4) dopamine repletion is sufficient to restore striatal activity and invigorate movement. Reproduced with permission from Panigrahi et al., Cell, 2015 [38].

Figure 5.

Association between Dopamine D₂ receptor availability (B_max/K_d) in the caudate and the putamen and performance on the finger tapping test. Reproduced with permission from Volkow et al., Am J Psychiatry, 1998 [69].

Figure 6.. Mean increase in motor evoked potential (MEP) amplitude after intermittent theta-burst stimulation of healthy adults of different ages.

Studies have indicated that cortical plasticity to theta-burst stimulation is largely dependent on striatal dopaminergic neuron function, and while these findings are not statistically different likely due to the small sample size, it should be noted that a robust mean difference between the older adults and their younger counterparts was observed providing further support to the notion of age-related impairments in striatal dopaminergic neuron function. Figure created from data presented in Di Lazzaro et. al, J Physiol, 2008 [82].

Figure 7.. Young individuals with faster reaching movements also generate faster head movements.

Findings of this nature have led to the assertion that movement vigor may be a trait, cutting across modalities of motor control, with the vigor with which a movement is performed being dependent on the subjective evaluation of reward, effort, and time [40,83]. Reproduced with permission from Shadmehr et al., Trends in Neurosci, 2019 [40]. (note: original data represented in this figure is from Reppert et al., J Neurophysiol, 2018 [83]).