Epicranial electrical stimulation improves non-navigational spatial memory in macaque monkeys

The hippocampus and medial temporal lobe are crucial for spatial memory, and their dysfunction is linked to Alzheimer's disease (AD), with changes detectable even in preclinical stages. Recently, neuromodulation has gained interest as a potential treatment due to its beneficial effects on AD pathology and cognitive performance. However, outcomes vary significantly based on stimulation parameters and study conditions, and evidence from large animal models remains limited. To assess whether epicranial current stimulation (ECS) at 40 Hz can improve non-navigational spatial memory and hippocampal activations. Three rhesus macaques were implanted with spiral platinum electrodes bilaterally on the skull and were trained in a non-navigational spatial memory task. ECS was applied at 40 Hz or at 10 Hz and performance across multiple sessions was evaluated. We further performed ECS during fMRI to examine the spread of activations caused by ECS across the brain in a block-design experiment. ECS at 40 Hz improved performance in a non-navigational spatial memory task, while 10 Hz ECS had minimal or negative effects. Concurrent ECS-fMRI showed extensive brain activations at 40 Hz, including significant hippocampal activations, which was not observed at 10 Hz. Our results show that ECS could be a minimally-invasive and effective approach to improve memory performance and activate the hippocampus. ECS could represent a potential treatment for patients suffering from memory impairment. • 40 Hz ECS can improve performance in a non-navigational spatial memory task. • 40 Hz ECS elicits widespread brain activations, both cortical and subcortical, while 10 Hz ECS caused minimal activation. • ECS could be a minimally-invasive approach to modulate subcortical brain structures.