Large-Vessel Venous Signal Confounds Apparent Amygdala Activation in BOLD fMRI

Amygdala responses are widely reported in BOLD fMRI studies of human emotions and mood disorders. Although modern acquisition methods have improved image quality, the hemodynamic nature of the BOLD signal continues to complicate interpretation of these responses. Across an array of both visual and auditory tasks, we here show that apparent amygdala BOLD signal is substantially confounded by signal from nearby deep veins, including the basal vein of Rosenthal. In contrast to prior work, we show that the amygdala, when engaged, is the leading but not exclusive contributor to this venous signal. Across the tested conditions, this signal was sensitive to, but not specific for, amygdala engagement. This confound mislocalizes apparent activation and prevents reliable attribution of signal to amygdala subnuclei with conventional BOLD fMRI. We further show that spatial smoothing exacerbates this mislocalization by merging peri-amygdalar venous signal with the anatomical amygdala. We reproduce our findings from precision imaging in a larger sample obtained from the Human Connectome Project. While broad conclusions about amygdala engagement remain largely valid when based on unsmoothed signal within the anatomical amygdala, further conclusions about subnuclear function drawn from conventional fMRI alone warrant considerable caution.