Stereotactic rodent-to-human approximation of the mesencephalic cuneiform nucleus to guide deep brain stimulation

Permanent gait dysfunction is common after severe spinal cord injury. It is attributed to insufficient excitation and control of sublesional spinal locomotor centers due to disrupted descending input. Deep brain stimulation of the cuneiform nucleus has emerged as a promising approach to restore locomotion in individuals with incomplete lesions. It increases reticulospinal drive and was shown to improve gait in preclinical rodent models of spinal cord injury. Early human trials are underway (clinicaltrials.gov, NCT03053791, NCT07109804). The cuneiform nucleus and the pedunculopontine nucleus form the mesencephalic locomotor region, a gait control center evolutionarily conserved across species. Given the proximity to several other critical brainstem structures, precise placement of stimulation electrodes is essential. Yet, empirical human data on optimal stimulation sites in this novel target are scarce.

The study aimed to translate the stereotactic localization of the functionally relevant area of the rodent cuneiform nucleus to application in humans considering the brainstem's phylogenetic conservation across vertebrate species. The overall goal was to provide heuristically derived, orientational coordinates and landmarks to guide human electrode implantation.

First, the key functional area of the rat cuneiform nucleus was confirmed by electrical mapping, and the anatomical sites of the rodent (rat and mouse) cuneiform and pedunculopontine nuclei were delineated by in situ hybridization for mRNA of the respective markers neurotensin and choline acetyltransferase. Labeled cell distributions were reconstructed in a stereotactic coordinate system. Anatomical landmarks to localize the cuneiform nucleus and their relative spatial relationships were then applied to the human brainstem, also considering published stimulation sites of individuals who previously underwent stimulation of the cuneiform or pedunculopontine nucleus. Stereotactic targeting of the cuneiform nucleus was simulated on postmortem magnetic resonance scans of human brains and stereotactic coordinates were extracted.

Cross-species evaluation enabled derivation of an anatomy-anchored estimate of implantation coordinates for deep brain stimulation of the human cuneiform nucleus. Comparison with the electrode locations of previously implanted individuals informed refinement of target specification for future patients.

This study provides heuristic coordinates to target the cuneiform nucleus for deep brain stimulation. Given that localization of the human cuneiform nucleus was only indirect and that cross-species translation of coordinates is inherently approximate, the proposed coordinates and landmarks should be regarded as guidance. They do not replace consideration of individual anatomical differences and are expected to be refined as clinical experience grows.