Orientation of Temporal Interference for Non-invasive Deep Brain Stimulation in Epilepsy

In patients with focal drug-resistant epilepsy, electrical stimulation from intracranial electrodes is frequently used for the localization of seizure onset zones and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. Here, we demonstrate an alternative technique relying exclusively on non-penetrating surface electrodes, namely an orientation-tunable form of temporally interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. Additionally, we demonstrate the use of Pulse-width-modulation of square waves as an alternative to sine waves for TI stimulation. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally invasive temporally interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue and overcoming several limitations of other non-invasive stimulation methods in epilepsy, such as transcranial magnetic stimulation (TMS).

Probing cortical excitability under GABAergic modulation

Cortical excitability, the variable response to a given cortical input, is widely studied in neuroscience, from slice experiments and in silico modeling work to human clinical settings. However, a unifying definition and a translational approach to the phenomenon are currently lacking. For example, at the onset of epileptic seizures, cortical excitability may impair resilience to perturbations (external or endogenous). In this study, we tested in vivo whether changes in cortical excitability quantified as evoked response to small perturbation corresponded to changes in resilience to larger perturbations. To do so, we used both cell-type circuit specific optogenetic stimulation in mice and direct intracranial stimulation in one human subject and quantified 1) evoked cortical responses to single pulses of varying intensity, and 2) evoked cortical facilitation and suppression to paired pulses at varying intervals. In the presence of a gamma-Aminobutyric acid (GABA) agonist or antagonist, we found that 1) cortical response to single pulses and 2) cortical facilitation decreased and increased, respectively. Additionally, using trains of opto-pulses in mice in the presence of a GABA agonist, we found increased resilience to the induction of seizures. With this study, we provide evidence for a tight correlation between cortical excitability and resilience, exploring a range of cortical dynamics, from physiological excitability, to pathological discharges. Our study carried out with two different stimulation methods in two species suggests that varying cortical excitability can be tracked with simple protocols involving minute short-lived perturbative stimuli.

Intracranial brain stimulation modulates fMRI-based network switching

SummaryThe extent to which resting-state fMRI (rsfMRI) reflects direct neuronal changes remains unknown. Using 160 simultaneous rsfMRI and intracranial brain stimulation recordings acquired in 26 individuals with epilepsy (with varying electrode locations), we tested whether brain networks dynamically change during intracranial brain stimulation, aiming to establish whether switching between brain networks is reduced during intracranial brain stimulation. As the brain spontaneously switches between a repertoire of intrinsic functional network configurations and the rate of switching is typically increased in brain disorders, we hypothesised that intracranial stimulation would reduce the brain’s switching rate, thus potentially normalising aberrant brain network dynamics. To test this hypothesis, we quantified the rate that brain regions changed networks over time in response to brain stimulation, using network switching applied to multilayer modularity analysis of time-resolved rsfMRI connectivity. Network switching was significantly decreased during epochs with brain stimulation compared to epochs with no brain stimulation. The initial stimulation onset of brain stimulation was associated with the greatest decrease in network switching, followed by a more consistent reduction in network switching throughout the scans. These changes were most commonly observed in cortical networks spatially distant from the stimulation targets. Our results suggest that neuronal perturbation is likely to modulate large-scale brain networks, and multilayer network modelling may be used to inform the clinical efficacy of brain stimulation in neurological disease.HighlightsrsfMRI network switching is attenuated during intracranial brain stimulationStimulation-induced switching is observed distant from electrode targetsOur results are validated across a range of network parametersNetwork models may inform clinical efficacy of brain stimulation

Orientation of Temporal Interference for Non-Invasive Deep Brain Stimulation in Epilepsy

In patients with focal drug-resistant epilepsy, electrical stimulation from intracranial electrodes is frequently used for the localization of seizure onset zones and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. Here, we demonstrate an alternative technique relying exclusively on nonpenetrating surface electrodes, namely an orientation-tunable form of temporally-interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. Additionally, we demonstrate the use of square waves as an alternative to sine waves for TI stimulation. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally-invasive temporally-interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue.

CLoSES: A platform for closed-loop intracranial stimulation in humans

Targeted interrogation of brain networks through invasive brain stimulation has become an increasingly important research tool as well as a therapeutic modality. The majority of work with this emerging capability has been focused on open-loop approaches. Closed-loop techniques, however, could improve neuromodulatory therapies and research investigations by optimizing stimulation approaches using neurally informed, personalized targets. Specifically, closed-loop direct electrical stimulation tests in humans performed during semi-chronic electrode implantation in patients with refractory epilepsy could help deepen our understanding of basic research questions as well as the mechanisms and treatment solutions for many neuropsychiatric diseases.However, implementing closed-loop systems is challenging. In particular, during intracranial epilepsy monitoring, electrodes are implanted exclusively for clinical reasons. Thus, detection and stimulation sites must be participant- and task-specific. In addition, the system must run in parallel with clinical systems, integrate seamlessly with existing setups, and ensure safety features. A robust, yet flexible platform is required to perform different tests in a single participant and to comply with clinical settings.In order to investigate closed-loop stimulation for research and therapeutic use, we developed a Closed-Loop System for Electrical Stimulation (CLoSES) that computes neural features which are then used in a decision algorithm to trigger stimulation in near real-time. To summarize CLoSES, intracranial EEG signals are acquired, band-pass filtered, and local and network features are continuously computed. If target features are detected (e.g. above a preset threshold for certain duration), stimulation is triggered. An added benefit is the flexibility of CLoSES. Not only could the system trigger stimulation while detecting real-time neural features, but we incorporated a pipeline wherein we used an encoder/decoder model to estimate a hidden cognitive state from the neural features. Other features include randomly timed stimulation, which percentage of biomarker detections produce stimulation, and safety refractory periods.CLoSES has been successfully used in twelve patients with implanted depth electrodes in the epilepsy monitoring unit during cognitive tasks, spindle detection during sleep, and epileptic activity detection. CLoSES provides a flexible platform to implement a variety of closed-loop experimental paradigms in humans. We anticipate that probing neural dynamics and interaction between brain states and stimulation responses with CLoSES will lead to novel insights into the mechanism of normal and pathological brain activity, the discovery and evaluation of potential electrographic biomarkers of neurological and psychiatric disorders, and the development and testing of patient-specific stimulation targets and control signals before implanting a therapeutic device.