Locus coeruleus features are linked to vagus nerve stimulation response in drug-resistant epilepsy

Abstract

The locus coeruleus-norepinephrine system is thought to be involved in the clinical effects of vagus nerve stimulation. This system is known to prevent seizure development and induce long-term plastic changes, particularly with the release of norepinephrine in the hippocampus. However, the requisites to become responder to the therapy and the mechanisms of action are still under investigation. Using MRI, we assessed the structural and functional characteristics of the locus coeruleus and microstructural properties of locus coeruleus-hippocampus white matter tracts in patients with drug-resistant epilepsy responding or not to the therapy. Twenty-three drug-resistant epileptic patients with cervical vagus nerve stimulation were recruited for this pilot study, including 13 responders or partial responders and 10 non-responders. A dedicated structural MRI acquisition allowed in vivo localization of the locus coeruleus and computation of its contrast (an accepted marker of LC integrity). Locus coeruleus activity was estimated using functional MRI during an auditory oddball task. Finally, multi-shell diffusion MRI was used to estimate the structural properties of locus coeruleus-hippocampus tracts. These characteristics were compared between responders/partial responders and non-responders and their association with therapy duration was also explored. In patients with a better response to the therapy, trends toward a lower activity and a higher contrast were found in the left medial and right caudal portions of the locus coeruleus, respectively. An increased locus coeruleus contrast, bilaterally over its medial portions, correlated with duration of the treatment. Finally, a higher integrity of locus coeruleus-hippocampus connections was found in patients with a better response to the treatment. These new insights into the neurobiology of vagus nerve stimulation may provide novel markers of the response to the treatment and may reflect neuroplasticity effects occurring in the brain following the implantation.

Keywords: biomarker; epilepsy; locus coeruleus; magnetic resonance imaging; vagus nerve stimulation.

FIGURE 1

Extraction of the LC contrast. (A) Registration of the LC slab to the structural T1-anatomical image (axial, sagittal and coronal views); (B) computation of the intersection of the LC masks of two independent raters; (C) subdivision of the LC into rostral—25 upper % (blue), medial—50 middle % (red), and caudal—25 lower % (green); (D) selection of the voxel with the highest intensity for each axial slice; (E) centering of a 5-voxel cross on the voxel with the highest intensity; (F) definition of a slice-corresponding reference region in the pons (axial view), and final 3D reference region (sagittal view).

FIGURE 2

LC response to target stimuli in patients responding (or partially responding) and not responding to VNS treatment. Activity in the rostral, medial and caudal portions of the (A) left LC (all patients included), (B) right LC (all patients included), (C) left LC (only patients with a good accuracy to the task, i.e., > 90%) and (D) right LC (only patients with a good accuracy to the task, i.e., > 90%), in non-responders (NR) and responders (R)/partial responders (PR). Refer to text and Supplementary Material 3 for full statistical outputs of LM models.

FIGURE 3

Linear regressions between contrasts in LC subparts and therapy duration. Linear regressions for the rostral–medial and caudal left (blue circles), right (orange stars) and mean over left and right (green diamond) LC and therapy duration (expressed in months). Refer to Supplementary Material 3 for statistical output of the LM.

FIGURE 4

Tractography of the left LC-hippocampus connections in a representative subject. Orange: left locus coeruleus, purple: left hippocampus. The color of the tracts reflects the directionality of the fibers.

FIGURE 5

Integrity of LC-hippocampus connections in patients responding (or partially responding) and not responding to VNS treatment. First row: Boxplots showing the difference in diffusion metrics in left LC-hippocampus connections between responders (R)/partial responders (PR) and non-responders (NR). Second row: Boxplots showing the difference in diffusion metrics in right LC-hippocampus connections between R/PR and NR. Refer to text and Supplementary Material 3 for full statistical outputs of LM models.