The aging cerebellum: how differences in inhibition and neurometabolite levels relate to motor function

Abstract

The global population is aging at an unprecedented rate, with life expectancy increasing significantly over the past decades. However, this rise in longevity has not been matched by a similar increase in "healthy life expectancy," implying that many additional years are spent in suboptimal or poor health. A key concern in this demographic shift is the decline in motor function, even in the absence of overt disease. Older adults often face challenges in daily activities due to age-related changes in cognitive and motor control, which are linked to alterations, among others, within the brain. Understanding the neural mechanisms underlying this motor decline is essential for promoting healthy aging and maintaining independence. The cerebellum is a crucial brain region for motor coordination and learning, and it has been suggested to be implicated in aging. This Ph.D. thesis specifically investigated age-related differences in the cerebellum and their impact on motor control and learning. Our research aimed to identify how cerebellar differences contribute to the observed motor difficulties in older adults by examining effective cerebellar-primary motor cortex connectivity, cerebellar neurochemistry, and various aspects of motor performance and learning. To achieve this, we employed multiple measurement techniques. In particular, we used dual-site transcranial magnetic stimulation (ds-TMS) to assess cerebellar brain inhibition (CBI), a measure reflecting the inhibitory influence of the cerebellum on the primary motor cortex. CBI was evaluated both at rest and dynamically during a bimanual motor task to capture how cerebellarcortical interactions are modulated. Apart from these investigations, we evaluated participants' motor capabilities using a battery of tasks, including simple and choice reaction time and a stopsignal task to evaluate response inhibition. In a second experiment, we utilized magnetic resonance spectroscopy (MRS) to quantify key neurometabolites within the cerebellum: gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter; Glx (glutamine and glutamate), representing excitatory neurotransmission; and glutathione (GSH), a critical antioxidant. We assessed both baseline concentrations and task-related modulations of GABA and Glx. Specifically, we measured GABA and Glx levels during the execution of a bimanual coordination task to evaluate both performance as well as short-term motor learning. Our findings revealed interesting insights into cerebellar aging. As expected, older adults consistently demonstrated reduced motor performance across all tasks, exhibiting slower reaction times, increased error rates, diminished reactive inhibition, and poorer accuracy compared to younger adults. Their bimanual coordination was also impaired, and they showed a flatter shortterm learning curve. Crucially, despite these behavioral declines, older adults retained the fundamental capacity for motor learning, albeit at a slower rate.