[mattkrause]

That depends immensely on the type of effect you're looking for.

Within-subject effects (this happens when one does A, but not when doing B) can be fine with small sample sizes, especially if you can repeat variations on A and B many times. This is pretty common in task-based fMRI. Indeed, I'm not sure why you need >2 participants expect to show that the principle is relatively generalizable.

Between-subject comparisons (type A people have this feature, type B people don't) are the problem because people differ in lots of ways and each contributes one measurement, so you have no real way to control for all that extra variation.

[D-Machine]

Precisely, and agreed 100%. We need far more within-subject designs.

You would still in general need many subjects to show the same basic within-subject patterns if you want to claim the pattern is "generalizable", in the sense of "may generalize to most people", but, precisely depending on what you are looking at here, and the strength of the effect, of course you may not need nearly as much participants as in strictly between-subject designs.

With the low test-retest reliability of task fMRI, in general, even in adults, this also means that strictly one-off within-subject designs are also not enough, for certain claims. One sort of has to demonstrate that even the within-subject effect is stable too. This may or may not be plausible for certain things, but it really needs to be considered more regularly and explicitly.

[SubiculumCode]

Between-subject heterogeneity is a major challenge in neuroimaging. As a developmental researcher, I've found that in structural volumetrics, even after controlling for total brain size, individual variance remains so large that age-brain associations are often difficult to detect and frequently differ between moderately sized cohorts (n=150-300). However, with longitudinal data where each subject serves as their own control, the power to detect change increases substantially—all that between-subject variance disappears with random intercept/slope mixed models. It's striking.

Task-based fMRI has similar individual variability, but with an added complication: adaptive cognition. Once you've performed a task, your brain responds differently the second time. This happens when studies reuse test questions—which is why psychological research develops parallel forms. But adaptation occurs even with parallel forms (commonly used in fMRI for counterbalancing and repeated assessment) because people learn the task type itself. Adaptation even happens within a single scanning session, where BOLD signal amplitude for the same condition typically decreases over time.

These adaptation effects contaminate ICC test-retest reliability estimates when applied naively, as if the brain weren't an organ designed to dynamically respond to its environment. Therefore, some apparent "unreliability" may not reflect the measurement instrument (fMRI) at all, but rather highlights the failures in how we analyze and conceptualize task responses over time.