Most of what we know about how the human brain functions is based on studies of brain activity in single individuals under very controlled parameters. Conventional neuroimaging is performed in a scanner environment using functional magnetic resonance imaging (fMRI) in which participants are constrained in an MRI bore that includes loud high-pitched noises, a head-mounted contraption conducive to claustrophobia and anxiety, and instructions to avoid any head movements or talking. However, recent applications of optical imaging technology using functional near-infrared spectroscopy (fNIRS) provide head-mounted detectors, called optodes, that acquire hemodynamic signals, which are the common proxy for neural activity. The advantage of neuroimaging technology capable of detecting neural events during live interactions is a game-changer for social neuroscience. During the COVID era, Zoom (and similar online video media) provided an innovative solution to maintaining necessary connections and communications. An investigation conducted at Yale School of Medicine employed fNIRS and two-person technology setups to compare the neural responses to live faces during in-person and video-call conditions. The investigation developed a new generation of integrated functional neuroimaging technologies, including NIR spectroscopy, fNIRS, and electroencephalography (EEG). Behavioral measures were acquired simultaneously on pairs of individuals during live interactive experimental conditions. In this recent study, dyads (pairs of individuals) viewed each other’s faces for brief 3-s intervals in two conditions: in-person and on a Zoom-like platform. Behavioral differences included longer dwell times for the in-person face than for the online-face condition, possibly indicating an increase of visual information acquired during live-face interaction. Increased pupil diameters in the live face were consistent with the interpretation of increased levels of arousal for live faces. Consistent with these behavioral findings, signal increases acquired by fNIRS were observed in the dorsal parietal regions of the brain for the real faces. And increased cross-brain synchrony, i.e., the correspondence of neural signal between the partners, was observed within the same dorsal parietal regions for the live in-person face condition. The robust neural, physiological, and behavioral differences observed in this investigation highlight the profound brain consequences depending on which media is employed. However, future research is necessary to understand the meaning of these differences and the resulting effects on education, telemedicine, conflict resolution, group meetings, and business transactions. Online interaction is here to stay. It is up to researchers to chart a path for how industry, and society, can make the most of it. Meet the author Joy Hirsch, Ph.D., is professor of psychiatry, comparative medicine, and neuroscience at Yale School of Medicine. She is also professor of neuroscience, ex officio, in the Department of Medical Physics and Biomedical Engineering at University College London. Her laboratory has developed multimodal two-person neuroimaging technology that is based on NIR spectroscopy (NIRS), functional NIRS, and configured for real-time, face-to-face dialogue interactions between humans; email: joy.hirsch@yale.edu. The views expressed in ‘BioOpinion’ are solely those of the author and do not necessarily represent those of Photonics Media. To submit a BioOpinion, send a few sentences outlining the proposed topic to doug.farmer@photonics.com. Accepted submissions will be reviewed and edited for clarity, accuracy, length, and conformity to Photonics Media style.