The Neurostimulationist will see you now: prescribing direct electrical stimulation therapies for the human brain in epilepsy and beyond.

As the pace of research in implantable neurotechnology increases, it is important to take a step back and see if the promise lives up to our intentions. While direct electrical stimulation applied intracranially has been used for the treatment of various neurological disorders, such as Parkinson's, epilepsy, clinical depression, and Obsessive-compulsive disorder, the effectiveness can be highly variable. One perspective is that the inability to consistently treat these neurological disorders in a standardized way is due to multiple, interlaced factors, including stimulation parameters, location, and differences in underlying network connectivity, leading to a trial-and-error stimulation approach in the clinic.

Theta-burst direct electrical stimulation remodels human brain networks.

Theta-burst stimulation (TBS), a patterned brain stimulation technique that mimics rhythmic bursts of 3-8 Hz endogenous brain rhythms, has emerged as a promising therapeutic approach for treating a wide range of brain disorders, though the neural mechanism of TBS action remains poorly understood. We investigated the neural effects of TBS using intracranial EEG (iEEG) in 10 pre-surgical epilepsy participants undergoing intracranial monitoring. Here we show that individual bursts of direct electrical TBS at 29 frontal and temporal sites evoked strong neural responses spanning broad cortical regions.

Simultaneous invasive and non-invasive recordings in humans: A novel Rosetta stone for deciphering brain activity.

Simultaneous noninvasive and invasive electrophysiological recordings provide a unique opportunity to achieve a comprehensive understanding of human brain activity, much like a Rosetta stone for human neuroscience. In this review we focus on the increasingly-used powerful combination of intracranial electroencephalography (iEEG) with scalp electroencephalography (EEG) or magnetoencephalography (MEG). We first provide practical insight on how to achieve these technically challenging recordings.

Electrode Development for Epilepsy Diagnosis and Treatment.

Recording neural activity has been a critical aspect in the diagnosis and treatment of patients with epilepsy. For those with intractable epilepsy, intracranial neural monitoring has been of substantial importance. Clinically, however, methods for recording neural information have remained essentially unchanged for decades.

Differential cortical network engagement during states of un/consciousness in humans.

What happens in the human brain when we are unconscious? Despite substantial work, we are still unsure which brain regions are involved and how they are impacted when consciousness is disrupted. Using intracranial recordings and direct electrical stimulation, we mapped global, network, and regional involvement during wake vs. arousable unconsciousness (sleep) vs.

SEEGAtlas: A framework for the identification and classification of depth electrodes using clinical images.

Accurate localization, classification, and visualization of intracranial electrodes are fundamental for analyzing intracranial electrographic recordings. While manual contact localization is the most common approach, it is time-consuming, prone to errors, and is particularly challenging and subjective in low quality images, which are common in clinical practice. Automatically locating and interactively visualizing where each of the 100-200 individual contacts records in the brain is essential for understanding the neural origins of intracranial EEG.

Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology.

Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine's antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects.

Local and distant cortical responses to single pulse intracranial stimulation in the human brain are differentially modulated by specific stimulation parameters.

Background: Electrical neuromodulation via direct electrical stimulation (DES) is an increasingly common therapy for a wide variety of neuropsychiatric diseases. Unfortunately, therapeutic efficacy is inconsistent, likely due to our limited understanding of the relationship between the massive stimulation parameter space and brain tissue responses.

Objective: To better understand how different parameters induce varied neural responses, we systematically examined single pulse-induced cortico-cortico evoked potentials (CCEP) as a function of stimulation amplitude, duration, brain region, and whether grey or white matter was stimulated.

Closed-loop enhancement and neural decoding of cognitive control in humans.

Deficits in cognitive control-that is, in the ability to withhold a default pre-potent response in favour of a more adaptive choice-are common in depression, anxiety, addiction and other mental disorders. Here we report proof-of-concept evidence that, in participants undergoing intracranial epilepsy monitoring, closed-loop direct stimulation of the internal capsule or striatum, especially the dorsal sites, enhances the participants' cognitive control during a conflict task. We also show that closed-loop stimulation upon the detection of lapses in cognitive control produced larger behavioural changes than open-loop stimulation, and that task performance for single trials can be directly decoded from the activity of a small number of electrodes via neural features that are compatible with existing closed-loop brain implants.

Effect of Closed-Loop Direct Electrical Stimulation during Sleep Spindles in Humans.

Sleep spindles are transient oscillations in the brain related to sleep consolidation and memory. We investigated if brief, localized electrical pulses could perturb spindles on five human patients with intracerebral electrodes implanted for clinical purpose. We used a closed-loop setup to specifically detect spindles and stimulate in real-time during these events.

Distinguishing false and true positive detections of high frequency oscillations.

Objective: High frequency oscillations (HFOs) are a promising biomarker of tissue that instigates seizures. However, ambiguous data and random background fluctuations can cause any HFO detector (human or automated) to falsely label non-HFO data as an HFO (a false positive detection). The objective of this paper was to identify quantitative features of HFOs that distinguish between true and false positive detections.

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 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.

How the Human Brain Sleeps: Direct Cortical Recordings of Normal Brain Activity.

Objective: Regional variations in oscillatory activity during human sleep remain unknown. Using the unique ability of intracranial electroencephalography to study in situ brain physiology, this study assesses regional variations of electroencephalographic sleep activity and creates the first atlas of human sleep using recordings from the first sleep cycle.

Methods: Intracerebral electroencephalographic recordings with channels displaying physiological activity from nonlesional tissue were selected from 91 patients of 3 tertiary epilepsy centers.

Removing high-frequency oscillations: A prospective multicenter study on seizure outcome.

Objective: To evaluate the use of interictal high-frequency oscillations (HFOs) in epilepsy surgery for prediction of postsurgical seizure outcome in a prospective multicenter trial.

Methods: We hypothesized that a seizure-free outcome could be expected in patients in whom the surgical planning included the majority of HFO-generating brain tissue while a poor seizure outcome could be expected in patients in whom only a few such areas were planned to be resected. Fifty-two patients were included from 3 tertiary epilepsy centers during a 1-year period.

High-Frequency Oscillations in the Normal Human Brain.

Objective: High-frequency oscillations (HFOs) are a promising biomarker for the epileptogenic zone. It has not been possible, however, to differentiate physiological from pathological HFOs, and baseline rates of HFO occurrence vary substantially across brain regions. This project establishes region-specific normative values for physiological HFOs and high-frequency activity (HFA).

Atlas of the normal intracranial electroencephalogram: neurophysiological awake activity in different cortical areas.

Unlabelled: In contrast to scalp EEG, our knowledge of the normal physiological intracranial EEG activity is scarce. This multicentre study provides an atlas of normal intracranial EEG of the human brain during wakefulness. Here we present the results of power spectra analysis during wakefulness.

Tailoring epilepsy surgery with fast ripples in the intraoperative electrocorticogram.

Objective: Intraoperative electrocorticography (ECoG) can be used to delineate the resection area in epilepsy surgery. High-frequency oscillations (HFOs; 80-500 Hz) seem better biomarkers for epileptogenic tissue than spikes. We studied how HFOs and spikes in combined pre- and postresection ECoG predict surgical outcome in different tailoring approaches.

IBIS: an OR ready open-source platform for image-guided neurosurgery.

Purpose: Navigation systems commonly used in neurosurgery suffer from two main drawbacks: (1) their accuracy degrades over the course of the operation and (2) they require the surgeon to mentally map images from the monitor to the patient. In this paper, we introduce the Intraoperative Brain Imaging System (IBIS), an open-source image-guided neurosurgery research platform that implements a novel workflow where navigation accuracy is improved using tracked intraoperative ultrasound (iUS) and the visualization of navigation information is facilitated through the use of augmented reality (AR).

Methods: The IBIS platform allows a surgeon to capture tracked iUS images and use them to automatically update preoperative patient models and plans through fast GPU-based reconstruction and registration methods.

Spontaneous ripples in the hippocampus correlate with epileptogenicity and not memory function in patients with refractory epilepsy.

Introduction: High-frequency oscillations (HFOs, 80-500Hz) are newly-described EEG markers of epileptogenicity. The proportion of physiological and pathological HFOs is unclear, as frequency analysis is insufficient for separating the two types of events. For instance, ripples (80-250Hz) also occur physiologically during memory consolidation processes in medial temporal lobe structures.

Intracranial EEG potentials estimated from MEG sources: A new approach to correlate MEG and iEEG data in epilepsy.

Detection of epileptic spikes in MagnetoEncephaloGraphy (MEG) requires synchronized neuronal activity over a minimum of 4cm2. We previously validated the Maximum Entropy on the Mean (MEM) as a source localization able to recover the spatial extent of the epileptic spike generators. The purpose of this study was to evaluate quantitatively, using intracranial EEG (iEEG), the spatial extent recovered from MEG sources by estimating iEEG potentials generated by these MEG sources.

The morphology of high frequency oscillations (HFO) does not improve delineating the epileptogenic zone.

Objective: We hypothesized that high frequency oscillations (HFOs) with irregular amplitude and frequency more specifically reflect epileptogenicity than HFOs with stable amplitude and frequency.

Methods: We developed a fully automatic algorithm to detect HFOs and classify them based on their morphology, with types defined according to regularity in amplitude and frequency: type 1 with regular amplitude and frequency; type 2 with irregular amplitude, which could result from filtering of sharp spikes; type 3 with irregular frequency; and type 4 with irregular amplitude and frequency. We investigated the association of different HFO types with the seizure onset zone (SOZ), resected area and surgical outcome.

The identification of distinct high-frequency oscillations during spikes delineates the seizure onset zone better than high-frequency spectral power changes.

Objective: Interictal high-frequency oscillations (HFOs, 80-500Hz) can predict the seizure onset zone (SOZ), but visual detection of HFOs is time consuming. Time-frequency analysis can reveal large high-frequency (HF) power changes (80-500Hz) associated with inter-ictal spikes. The present study determines how well the rate of HFOs and spike-related HF power changes were co-localized with SOZ.

Improving recorded volume in mesial temporal lobe by optimizing stereotactic intracranial electrode implantation planning.

Purpose: Intracranial electrodes are sometimes implanted in patients with refractory epilepsy to identify epileptic foci and propagation. Maximal recording of EEG activity from regions suspected of seizure generation is paramount. However, the location of individual contacts cannot be considered with current manual planning approaches.

High frequency oscillations in intra-operative electrocorticography before and after epilepsy surgery.

Objective: Removal of brain tissue showing high frequency oscillations (HFOs; ripples: 80-250Hz and fast ripples: 250-500Hz) in preresection electrocorticography (preECoG) in epilepsy patients seems a predictor of good surgical outcome. We analyzed occurrence and localization of HFOs in intra-operative preECoG and postresection electrocorticography (postECoG).

Methods: HFOs were automatically detected in one-minute epochs of intra-operative ECoG sampled at 2048Hz of fourteen patients.