Cognitive Brain Research 14 (2002) 277–293 www.elsevier.com / locate / bres Research report Functional MRI of motor sequence acquisition: effects of learning stage and performance a,c, b,e b,d a * ¨ Ralph-Axel Muller , Natalia Kleinhans , Karen Pierce , Nobuko Kemmotsu , b,d Eric Courchesne a Department of Psychology, San Diego State University, MC1863, 6363 Alvarado Ct. [200, San Diego, CA 92120, USA b Laboratory for the Neuroscience of Autism, Children’ s Hospital Research Center, La Jolla, CA 92037, USA c Department of Cognitive Science, University of California, San Diego, CA 92093, USA d Department of Neurosciences, University of California, San Diego, CA 92093, USA e Joint Doctoral Program in Clinical Psychology, San Diego State University and University of California, San Diego, CA 92120, USA Accepted 8 March 2002 Abstract Neural networks of motor control are well understood and the motor domain therefore lends itself to the study of learning. Neuroimaging of motor learning has demonstrated fronto-parietal, subcortical, and cerebellar involvement. However, there is conflicting evidence on the specific functional contributions of individual regions and their relative importance for early and advanced stages of learning. Using functional MRI (fMRI), we examined hemodynamic effects in seven right-handed men during brief episodes of explicit learning of novel six-digit sequences (experiments 1 and 2) and during prolonged learning of an eight-digit sequence (experiment 3), all performed with the dominant hand. Brief episodes of new learning were predominantly associated with bilateral activations in premotor and supplementary motor areas, superior and inferior parietal cortices, and anterior cerebellum. In experiment 2, which included a control condition matched for complexity of motor execution, we also found unexpectedly strong activation in the bilateral inferior frontal lobes. In experiment 3, analysis of task by learning stage interactions showed greater involvement of the bilateral superior parietal lobes, the right middle frontal gyrus, and the left caudate nucleus during early stages, whereas left occipito-temporal and superior frontal cortex as well as the bilateral parahippocampal region were more activated during late learning stages. Analysis of task by performance interactions (based on each subject’s response times and accuracy during each scan) showed effects in bilateral fronto-polar, right hippocampal, and anterior cerebellar regions associated with high levels of performance, as well as inverse effects in bilateral occipito-parietal regions. We conclude that superior parietal and occipital regions are most intensely involved in visually driven explicit digit sequence learning during early stages and low performance, whereas later stages of acquisition and higher levels of performance are characterized by stronger recruitment of prefrontal and mediotemporal regions.  2002 Elsevier Science B.V. All rights reserved. Theme: Motor systems and sensorimotor integration Topic: Cortex Keywords: Motor learning 1. Introduction domains such as language are of special interest for the study of learning in human cognitive neuroscience, the Animal models [10,32,46,52] and human neuroimaging lack of consensus on what constitutes the language pro- studies [3,44,54] have documented the mature brain’s cessing network in the mature brain adds to the complex- potential for plastic changes in neurofunctional organiza- ities of studying learning related changes. Networks of tion associated with learning. Although higher cognitive motor control, on the other hand, have been established by consistent findings in numerous functional neuroimaging studies [2,8,14,61,73,84], and the motor domain can *Corresponding author. Tel.: 11-619-594-5276; fax: 11-619-594- therefore serve as a relatively simple and solid setting for 1895. ¨ E-mail address: amueller@sciences.sdsu.edu (R.-A. Muller). the study of learning. 0926-6410 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0926-6410(02)00131-3