Repetition of letter strings leads to activation of and connectivity with word-related regions.

Individuals learn to read by gradually recognizing repeated letter combinations. However, it is unclear how or when neural mechanisms associated with repetition of basic stimuli (i.e., strings of letters) shift to involvement of higher-order language networks. The present study investigated this question by repeatedly presenting unfamiliar letter strings in a one-back matching task during an hour-long period. Activation patterns indicated that only brain areas associated with visual processing were activated during the early period, but additional regions that are usually associated with semantic and phonological processing in inferior frontal gyrus were recruited after stimuli became more familiar. Changes in activation were also observed in bilateral superior temporal cortex, also suggestive of a shift toward a more language-based processing strategy. Connectivity analyses reveal two distinct networks that correspond to phonological and visual processing, which may reflect the indirect and direct routes of reading. The phonological route maintained a similar degree of connectivity throughout the experiment, whereas visual areas increased connectivity with language areas as stimuli became more familiar, suggesting early recruitment of the direct route. This study provides insight about plasticity of the brain as individuals become familiar with unfamiliar combinations of letters (i.e., words in a new language, new acronyms) and has implications for engaging these linguistic networks during development of language remediation therapies.