In contrast, in our study the VTA/SN responses scaled with trial-by-trial precision-weighted PE about the stimulus category; these were neither reward-related, arousing nor novel (we kept repeating two to four face and house stimuli

in each study). One could think of VTA/SN activity reflecting conditional novelty (Bayesian surprise); however, this is not a tight link because ε2 is only related but not identical to Bayesian surprise (see Supplemental Experimental Procedures). An important caveat is that we cannot claim with certainty that the midbrain activation we found specifically reflects the activity of DA neurons Bortezomib in vitro in VTA/SN because this region is not homogenous in its cellular composition and also contains glutamatergic and GABAergic neurons (Nair-Roberts et al., 2008). In particular, our anatomical mask does not distinguish pars compacta and pars reticularis of the SN; the latter contains GABAergic neurons whose contribution to the blood oxygen level-dependent (BOLD) signal is not well understood (Logothetis, 2008). While multimodal investigations have demonstrated good correspondence between striatal DA release and BOLD signal in VTA/SN in response to reward

PEs or novel stimuli (see Düzel et al., 2009 for review), this relation still remains to be established for sensory PEs. Similar caveats apply to our findings on the basal forebrain, BMS-354825 purchase which also contains other neurons than only before cholinergic ones (Zaborszky et al., 2008). With this caveat in mind, our study suggests that in humans the dopaminergic midbrain may not only encode PEs about reward, but also precision-weighted PEs about purely sensory outcomes. To our knowledge, similar midbrain activations have not been reported in previous studies on reward-unrelated learning (e.g., d’Acremont et al., 2013 and Gläscher et al., 2010). Notably, our experiments were designed to detect brainstem

activations, including an optimized fMRI sequence and careful correction for physiological (cardiac and respiratory) noise. Last but not least, our studies had considerably larger sample sizes, and consequently higher statistical power, than previous fMRI studies on reward-unrelated learning. It is worth mentioning that the recent study by Ide et al. (2013), which reports activity for unsigned PEs (Bayesian surprise) in ACC during a Go/NoGo task, does show a midbrain activation (their Figure 3); however, this is not a sensory PE but reflects a main effect of stop versus go trials. Another recent fMRI study (Payzan-LeNestour et al., 2013) on neuromodulatory mechanisms during learning focused on different forms of uncertainty and on the noradrenergic system but did not report any findings related to PEs, nor to DA or ACh, as in this study. In animal studies, disentangling responses to sensory and reward aspects of stimuli is often difficult because stimulus-bound reward are required to maintain motivation (Maunsell, 2004).