Stimulus-evoked neural activity is attenuated upon stimulus repetition ('repetition suppression'), a phenomenon attributed to largely automatic processes in sensory neurons. By manipulating the likelihood of stimulus repetition, we show that repetition suppression in the human brain is reduced when stimulus repetitions are improbable (and thus, unexpected). These data suggest that repetition suppression reflects a relative reduction in top-down perceptual 'prediction error' when processing an expected compared to an unexpected stimulus.Stimulus-specific repetition suppression (RS) -the relative attenuation in neural signal evoked by the repeated occurrence of a stimulus -is among the best-known neural phenomena [1][2][3][4] , and has been widely employed in functional magnetic resonance imaging (fMRI) studies to define functional properties of brain regions 5,6 and explore neural substrates of behavioral priming effects 2,4 . However, the neurocomputational basis for RS remains controversial 1 . Two influential theories view RS as a relatively automatic consequence of the bottom-up flow of perceptual information through sensory cortex: either neurons tuned to the repeated stimulus fatigue 1 , or subsequent presentations of a stimulus are encoded more sparsely (and efficiently), leading to a sharpening in the population of neurons recruited 4,7 . By contrast, a recent model of perceptual inference casts RS as a consequence of top-down perceptual expectations 2,8 : here, RS reflects a reduction in perceptual 'prediction error' (the neural signal evoked by a mismatch between expected and observed percepts) that occurs when sensory evidence conforms to a more probable (previously seen) compared to a less probable (novel) percept. Unlike other theories, the prediction error model holds that RS will vary with contextual factors that affect subjects' perceptual expectations, and suggests that RS will be reduced under conditions where stimulus repetitions are unexpected.We created such a situation by presenting subjects (n = 16), who had provided informed written consent, on each trial with either the same face twice, or two different faces, in two experimental contexts -one where repetitions occurred more frequently than alternations, and one where the reverse was the case. Importantly, all face exemplars were trial-unique, such that the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript probability of a repetition per se, and not the frequency of repetition of a specific face, varied between blocks ( Fig. 1a and Supplementary Methods online). Incidental to this manipulation, subjects were required to make a speeded response to occasional inverted faces ('targets') 9 . Limiting our analysis to non-target trials, we measured how face-sensitive visual cortex responded to face repetitions ('rep trials') and face alternations ('alt trials') that were either expected (in 'REP BLOCKS') or unexpected (in 'ALT BLOCKS'), comparing these estimates in 2 × 2 factorial mixed block/event-related desi...

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Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of intranasal insulin detemir.