Towards network-guided neuromodulation for epilepsy

Abstract

Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce seizures in adults with focal-onset epilepsy; and there is emerging evidence for their efficacy in children and generalized-onset seizure disorders. The convergence of these advancing fields is driving an era of 'network-guided neuromodulation' for epilepsy. In this review, we distil the current literature on network mechanisms underlying neurostimulation for epilepsy. We discuss the modulation of key 'propagation points' in the epileptogenic network, focusing primarily on thalamic nuclei targeted in current clinical practice. These include (i) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (ii) the centromedian nucleus of the thalamus, a target for both deep brain stimulation and responsive neurostimulation in generalized-onset epilepsies. We discuss briefly the networks associated with other emerging neuromodulation targets, such as the pulvinar of the thalamus, piriform cortex, septal area, subthalamic nucleus, cerebellum and others. We report synergistic findings garnered from multiple modalities of investigation that have revealed structural and functional networks associated with these propagation points - including scalp and invasive EEG, and diffusion and functional MRI. We also report on intracranial recordings from implanted devices which provide us data on the dynamic networks we are aiming to modulate. Finally, we review the continuing evolution of network-guided neuromodulation for epilepsy to accelerate progress towards two translational goals: (i) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (ii) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizure propagation through mapping and modulation of each patients' individual epileptogenic networks.

Keywords: connectivity; deep brain stimulation; epilepsy; networks; responsive neurostimulation.

Figure 1

Potential network modulation mechanisms of resective surgery, DBS and RNS using mesial temporal lobe epilepsy as an example of a focal epileptogenic network. This annotation uses coronal sections of an ex vivo brain from the BigBrain Project (open-source; https://bigbrainproject.org/).

Figure 2

Demonstration of the anatomical locations of the current propagation points/stimulation targets. (A) The ANT and (B) CMT. The images were created using LeadDBS^, with simulated trajectories within the BigBrain backdrop. The ANT (anteroventral) and CMT regions of interest and respective MNI coordinates were taken from the THOMAS atlas.^, The MNI coordinates are derived according to the centre of the regions of interest of the THOMAS atlas: anteroventral (right, 5, −5, 12; left, −5, −6, 12) and CMT (right, 10, −19,3; left, −10, −20,3). (C) Unconstrained fibres were seeded from each target using the normative fibre-tracking dataset of 32 adult participants from the Human Connectome Project.^,

Figure 3

A simplified schematic of the connections of the current and potential propagation points/stimulation targets. This figure demonstrates the common connections between these current and potential stimulation targets, including the ‘Circuit of Papez’. Current targets: ANT (red), CMT (blue). Potential targets: PC (yellow), septal area (SA; green), pulvinar (PUL; purple) and STN (orange). Connections with multiple colours show common connections with the respective stimulation targets.

Figure 4

Demonstration of the anatomical locations of some of the potential propagation points/stimulation targets: The PC (yellow), septal area (SA; green), pulvinar of thalamus (PUL; purple) and STN (orange). The images were created using LeadDBS^, with simulated trajectories within the BigBrain backdrop. The PC was manually segmented according to the Mai et al. atlas; the SA was manually segmented; the PUL is a reconstruction from the THOMAS atlas^, within LeadDBS and the STN is a reconstruction from the DISTAL atlas within LeadDBS.

Figure 5

Future directions of network-guided neuromodulation for epilepsy. (A) Seizures begin in the SOZ and propagate to a wider seizure network. Neurostimulation at stimulation targets prevent or limit the spread of seizure activity from the SOZ to the wider network. Panels B, C and D ask forward-thinking questions in network-guided neuromodulation epilepsy and draw on recent key studies.^,,,,,