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 epilepsy; and there is emerging evidence for their efficacy in children and generalized 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 (a) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (b) 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 revealed structural and functional networks associated with these propagation points – including scalp and invasive electroencephalography, diffusion and functional magnetic resonance imaging. 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 neurostimulation for epilepsy to accelerate progress towards two major goals: (1) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (2) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizures, limit seizure propagation through mapping and modulation of each patients’ individual epileptogenic networks.

Altered Cerebro-Cerebellar Effective Connectivity in New-Onset Juvenile Myoclonic Epilepsy

“…Moreover, our previous study made the first attempt to characterize the dynamic effective connectivity (DEC) in the DMN of patients with JME, demonstrating that the DEC between brain networks is very important in JME [ 20 ]. Epilepsy is regarded as a disruption of functional networks [ 21 ], and an increasing number of studies have suggested that cerebro-cerebellar interactions are important for the induction of JME [ 22 , 23 , 24 , 25 ].…”

Chronic modulation of human memory and thalamic-hippocampal theta activities

“…These results offer a potentially more effective strategy and/or new anatomical targets for therapeutic interventions for memory and cognitive deficits. In contrast to the widespread dispersed cortical networks, the thalamic nuclei connected to these networks are compact and condensed in confined volumes of neural tissue, making them suitable for local interventions like DBS to effectively modulate larger thalamocortical networks (65) . Future studies will determine the exact role of the ANT theta activities in memory and cognitive functions, employing closed-loop and long-term adaptive stimulation paradigms.…”

Multisite Thalamic Recordings to Characterize Seizure Propagation in the Human Brain

“…Our results show that different thalamic sites are involved differently in the very early stage of seizure propagation. This agrees with the extant literature, where thalamic participation in the epileptogenic networks of focal epilepsies has been documented (Ilyas et al ., 2022; Piper et al .,2022). Pioneering past studies have shown increased synchrony between cortical and thalamic ictal activity in temporal lobe seizures, and that in a majority of cases the thalamic activity was driven by cortical activity (Guye et al ., 2006).…”