Functional Ultrasound Imaging of the Human Spinal Cord

Abstract

The integration of functional responses in the human spinal cord into the nervous system is not well understood. Herein we demonstrate the first in-human functional ultrasound imaging (fUSI) of spinal cord response to epidural electrical stimulation. fUSI is a minimally invasive neuroimaging technique that can record blood flow at a level of spatial and temporal precision not previously achieved in the human spinal cord. By leveraging fUSI and epidural electrical spinal cord stimulation in patients who underwent surgery, we recorded and characterized for the first-time hemodynamic responses of the human spinal cord to an electrical neuromodulatory intervention commonly used for treating pain, and increasingly used for sensory-motor and autonomic functions. We found that the hemodynamic response to epidural stimulation reflects a spatiotemporal modulation of the spinal cord circuitry not previously recognized. The impact of this analytical capability is significant for several reasons. It offers a mechanism to assess blood flow changes with a new level of precision which can be obtained in real time under in vivo conditions. Additionally, we demonstrate that fUSI can successfully decode the spinal cord state in a single trial, which is of fundamental importance for developing real-time closed-loop neuromodulation systems. Also, we show that spinal cord hemodynamic changes due to epidural electrical stimulation occur primarily at the level of small vessels. Overall, our work is a critical step towards developing a vital technique to study spinal cord function and understand the potential effects of clinical neuromodulation for spinal cord and other neurological disorders.

Human spinal cord activation during filling and emptying of the bladder

“…Within this context, fUSI represents an emerging neuroimaging technology that utilizes ultrasound to monitor blood flow changes as an indirect readout of neuronal activity with high spatiotemporal resolution, penetration depth and sensitivity to slow blood flow motion. Originally developed for brain neuroimaging, fUSI has been recently expanded to study spinal neurovascular responses in small animals 26–29 and human patients 30 . Although these studies provide significant insights into better understanding the physiology of the spinal cord in sensory integrations, they are limited to artificial external stimulations, illustrating that fUSI is capable of detecting binary discrete spinal cord states– i.e., stimulation on vs. stimulation off.…”

“…Within this context, fUSI represents an emerging neuroimaging technology that utilizes ultrasound to monitor blood flow changes as an indirect readout of neuronal activity with high spatiotemporal resolution, penetration depth and sensitivity to slow blood flow motion. Originally developed for brain neuroimaging, fUSI has been recently expanded to study spinal neurovascular responses in small animals [26][27][28][29] and human patients 30 .…”

“…For this reason, most fUSI applications are minimally invasivewith few exceptions such as in young mice (8)(9)(10)(11)(12) weeks old with thin skull) 44 and in pediatric transfontanelle-imaging 17,45 . Surgical procedures to produce a craniotomy 21 or thinned-skull window 46 in brain research and laminectomy 26,30 in spinal cord research are required to harness the host of fUSI benefits.…”

“…A built-in phase-correlation based sub-pixel motion registration 52 and singular-valuedecomposition (SVD) based clutter filtering algorithms 53 , in the Iconeus One acquisition system were used to separate tissue motion signal from blood signal to generate relative pD signal intensity images 54 . We adopted rigid motion correction techniques 55 that have successfully been used in fUSI 21,23,30 and other neuroimaging studies [56][57][58] , to address potential physiological and motion artifacts unique to human spinal cord imaging. This was combined with in-house high frequency smoothing filtering.…”

“…Recently, fUSI was extended to study the spinal cord responses to electrical and mechanical stimulations in small animals and human patients [26][27][28][29][30] . Despite the significant contribution of these studies in understanding how the spinal cord reacts to external sensory stimulations, none of them have demonstrated spinal cord circuits associated with physiological functions (i.e., body processes) in humans.…”