Leveling up: improving power in fMRI by moving beyond cluster-level inference

Inference in neuroimaging commonly occurs at the level of "clusters" of neighboring voxels or connections, thought to reflect functionally specific brain areas. Yet increasingly large studies reveal effects that are shared throughout the brain, suggesting that reported clusters may only reflect the "tip of the iceberg" of underlying effects. Here, we empirically compare power of traditional levels of inference (edge and cluster) with broader levels of inference (network and whole-brain) by resampling functional connectivity data from the Human Connectome Project (n=40, 80, 120). Only network- and whole brain-level inference attained or surpassed "adequate" power ({beta}=80%) to detect an average effect, with almost double the power for network-compared with cluster-level procedures at more typical sample sizes. Likewise, effects tended to be widespread, and more widespread pooling resulted in stronger magnitude effects. Power also substantially increased when controlling FDR rather than FWER. Importantly, there may be similar implications for task-based activation analyses where effects are also increasingly understood to be widespread. However, increased power with broader levels of inference may diminish the specificity to localize effects, especially for non-task contexts. These findings underscore the benefit of shifting the scale of inference to better capture the underlying signal, which may unlock opportunities for discovery in human neuroimaging.