High-resolution label-free transcranial imaging of in vivo neural activity via interferometric measurement of tissue deformation

Rapid sub-nanometer neuronal deformations have been shown to occur as a consequence of action potentials in vitro, allowing for registration of discrete axonal and synaptic depolarizations and thus providing a novel signature for recording neural activity (1-3). We demonstrate that this signature can be extended to in vivo measurements through recording of rapid neuronal deformations on the population level with optical phase-based recordings. Complicating these measurements is the optical phase noise due to microvascular flow as well as the presence of significant tissue clutter (deformation) associated with physiologic processes (e.g., heart and respiratory rate). These recordings were acquired using a full-field holographic imaging system with spatiotemporal resolutions of less than 1 ms and 0.1 mm3 over a 3 mm diameter field of view (FOV). Our system demonstrates, for the first time, the ability to non-invasively record in vivo tissue deformation associated with population level neuronal activity. We confirmed this technique across a range of neural activation models, including direct epidural focal electrical stimulation (FES), activation of primary somatosensory cortex via whisker barrel stimulation, and pharmacologically-induced seizures. Calibrated displacement measurements of the associated tissue deformations provided additional insight into the underlying neural activation mechanisms. Collectively, we show that holographic imaging provides a pathway for high-resolution, label-free, non-invasive recording of transcranial in vivo neural activity at depth, making it highly advantageous for studying neural function and signaling.