Towards network-guided neuromodulation for epilepsy

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. Piper et al. describe the current state of network-guided neuromodulation for epilepsy and speculate on future directions. They review the mechanisms by which intracranial neurostimulation therapies reduce the frequency and severity of seizures and examine the neural networks underpinning current stimulation targets.

Automated summary

Epilepsy is a disorder of brain networks, and researchers are identifying critical nodes within these networks to target therapies for seizures. Intracranial neuromodulation has proven effective in reducing seizures in both adults and children, and the convergence of these fields is driving a new era of network-guided neuromodulation for epilepsy. This review summarizes the current literature on network mechanisms underlying neurostimulation for epilepsy, focusing on key propagation points in the epileptogenic network. The authors discuss current clinical targets, such as the thalamic nuclei, as well as emerging targets like the pulvinar of the thalamus and the cerebellum. They also report on findings from various modalities of investigation, including EEG and MRI, that reveal the structural and functional networks associated with these propagation points. The authors emphasize the importance of using network analyses to determine patient eligibility for neurostimulation and delivering personalized stimulation based on individual epileptogenic networks.