Neurobiology, not artifacts: Challenges and guidelines for imaging the high risk infant

&NA; The search for the brain‐basis of atypical development in human infants is challenging because the process of imaging and the generation of the MR signal itself relies on assumptions that reflect biophysical properties of the brain tissue. These assumptions are not inviolate, have been questioned by recent empirical evidence from high risk infant‐sibling studies, and to date remain largely underexamined at the between‐group level. In particular, I consider recent work showing that infants at High vs. Low familial risk (HR vs. LR, respectively) for developing Autism Spectrum Disorders (ASD) have atypical patterns of head movements during an MR scan that are functionally important—they are linked to future learning trajectories in toddlerhood. Addressing head movement issues in neuroimaging analyses in infant research as well as understanding the causes of these movements from a developmental perspective requires acknowledging the complexity of this endeavor. For example, head movement signatures in infants can interact with experimental task conditions (such as listening to language compared to sleeping), autism risk, and age. How can new knowledge about newborns' individual, subject‐specific behavioral differences which may impact MR signal acquisition and statistical inference ignite critical thinking for the field of infant brain imaging across the spectrum of typical and atypical development? Early behavioral differences between HR and LR infant cohorts that are often examples of “artifactual” confounds in MR work provide insight into nascent neurobiological differences, including biophysical tissue properties and hemodynamic response variability, in these and related populations at risk for atypical development. Are these neurobiological drivers of atypical development? This work identifies important knowledge gaps and suggests guidelines at the leading edge of baby imaging science to transform our understanding of atypical brain development in humans. The precise study of the neurobiological underpinnings of atypical development in humans calls for approaches including quantitative MRI (qMRI) pulse sequences, multi‐modal imaging (including DTI, MRS, as well as MEG), and infant‐specific HRF shapes when modeling BOLD signal. Graphical abstract Figure. No caption available. HighlightsHead movements during MR are sensitive to autism risk and task in 1–2 mo‐olds.Nuanced guidelines address head movement issues in neuroimaging analyses in infants.Early behavioral differences hint at atypical neurobiology.Biophysical brain properties can be studied using quantitative MRI.Use qMRI, multi‐modal imaging, and infant‐specific HRF to model BOLD.