GABA, Glx, and GSH in the Cerebellum: their role in motor performance and learning across age groups

Shanti Van Malderen^1,2*Melina Hehl^1,2Stefanie Verstraelen¹Robbe Breugelmans¹Georg Oeltzschner³Stephan P Swinnen²Koen Cuypers^1,2

• ¹University of Hasselt, Hasselt, Belgium
• ²KU Leuven, Leuven, Belgium
• ³Johns Hopkins, Baltimore, United States

The cerebellum is essential for motor control and learning, relying on structural and functional integrity. Age-related atrophy leads to Purkinje cell loss, but subtle neurochemical changes in GABA, Glx (glutamate + glutamine), and glutathione (GSH) may precede degeneration and contribute to motor decline.Methods: 25 younger (YA) and 25 older adults (OA) were included in this study. Magnetic resonance spectroscopy (MRS), using the MEGA-PRESS sequence, was used to investigate how age affects GABA,Glx and GSH levels in the right cerebellar hemisphere, and their relationship with motor performance, measured using a visuomotor bimanual tracking task (BTT).In line with previous work YA outperformed OA on both the simple and complex task variants of the BTT. Furthermore, YA demonstrated faster short-term motor learning as compared to OA. On the metabolic level, no significant age group differences in cerebellar GABA, Glx or GSH levels, nor any task-related modulation of GABA or Glx were observed. Additionally, neither baseline neurometabolite levels nor their modulation predicted motor performance or learning.Discussion: These results align with previous research suggesting that neurometabolic aging is region-specific, with the cerebellum potentially being more resilient due to its slower aging process. Since neither baseline nor task-related modulation of GABA, Glx, or GSH predicted motor performance or learning, cerebellar neurometabolite concentrations may not directly underlie age-related behavioral changes. Instead, volumetric decline and changes in structural and functional connectivity in the aging cerebellum may play a more significant role in motor decline as compared to neurochemical alterations. Nonetheless, it is important to consider that motor performance and learning rely on distributed brain networks-including cortical and subcortical structures-which also undergo age-related changes and may contribute to observed behavioral declines. While our findings do not support a direct role of cerebellar neurometabolite levels in age-related motor performance differences, they underscore the complexity of neurochemical aging.