INTRODUCTION fMRI findings have revealed the important insight that literacy-related learning triggers cognitive adaptation mechanisms manifesting themselves in increased BOLD responses during print processing tasks (Brem et al., 2010; Carreiras et al., 2009; Dehaene et al., 2010). It remains elusive, however, if the cortical plasticity effects of reading acquisition also lead to an intrinsic functional reorganization of neural circuits. METHODS Here, we used resting-state fMRI as a measure of domain-specific spontaneous neuronal activity to capture the impact of reading acquisition on the functional connectome (Honey et al., 2007; Lohmann et al., 2010; Raichle et al., 2001). In a controlled longitudinal intervention study, we taught 21 illiterate adults from Northern India for 6 months how to read Hindi scripts and compared their resting-state fMRI data with those acquired from a sample of 9 illiterates, matched for demographic and socioeconomic variables, that did not undergo such instruction. RESULTS Initially, we investigated at the whole-brain level, if the experience of becoming literate modifies network nodes of spontaneous hemodynamic activity. Therefore, we compared training-related differences in the degree centrality of BOLD signals between the groups (Zuo et al., 2012). A significant group by time interaction (tmax = 4.17, p < 0.005, corrected for cluster size) was found in a cluster extending from the right superior colliculus of the brainstem (+6, -30, -3) to the bilateral pulvinar nuclei of the thalamus (+6, -18, -3; -6, -21, -3). This interaction was characterized by a significant mean degree centrality increase in the trained group (t(1,20) = 8.55, p < 0.001) that did not appear in the untrained group which remained at its base level (t(1,8) = 0.14, p = 0.893). The cluster obtained from the degree centrality analysis was then used as a seed region in a voxel-wise functional connectivity analysis (Biswal et al., 1995). A significant group by time interaction (tmax = 4.45, p < 0.005, corrected for cluster size) emerged in the right occipital cortex (+24, -81, +15; +24, -93, +12; +33, -90, +3). The cortico-subcortical mean functional connectivity got significantly stronger in the group that took part in the reading program (z = 3.77, p < 0.001) but not in the group that remained illiterate (z = 0.77, p = 0.441). Individual slopes of cortico-subcortical connectivity were significantly associated with the improvement in letter knowledge (r = 0.40, p = 0.014) and with the improvement word reading ability (r = 0.38, p = 0.018). CONCLUSION Intrinsic hemodynamic activity changes driven by literacy occurred in subcortical low-level relay stations of the visual pathway and their functional connections to the occipital cortex. Accordingly, the visual system of beginning readers appears to go through fundamental modulations at earlier processing stages than suggested by previous event-related fMRI experiments. Our results add a new dimension to current concepts of the brain basis of reading and raise novel questions regarding the neural origin of developmental dyslexia.