Neurofeedback: One of today's techniques in psychiatry?

OBJECTIVES: Neurofeedback is a technique that aims to teach a subject to regulate a brain parameter measured by a technical interface to modulate his/her related brain and cognitive activities. However, the use of neurofeedback as a therapeutic tool for psychiatric disorders remains controversial. The aim of this review is to summarize and to comment the level of evidence of electroencephalogram (EEG) neurofeedback and real-time functional magnetic resonance imaging (fMRI) neurofeedback for therapeutic application in psychiatry. METHOD: Literature on neurofeedback and mental disorders but also on brain computer interfaces (BCI) used in the field of neurocognitive science has been considered by the group of expert of the Neurofeedback evaluation & training (NExT) section of the French Association of biological psychiatry and neuropsychopharmacology (AFPBN). RESULTS: Results show a potential efficacy of EEG-neurofeedback in the treatment of attentional-deficit/hyperactivity disorder (ADHD) in children, even if this is still debated. For other mental disorders, there is too limited research to warrant the use of EEG-neurofeedback in clinical practice. Regarding fMRI neurofeedback, the level of evidence remains too weak, for now, to justify clinical use. The literature review highlights various unclear points, such as indications (psychiatric disorders, pathophysiologic rationale), protocols (brain signals targeted, learning characteristics) and techniques (EEG, fMRI, signal processing). CONCLUSION: The field of neurofeedback involves psychiatrists, neurophysiologists and researchers in the field of brain computer interfaces. Future studies should determine the criteria for optimizing neurofeedback sessions. A better understanding of the learning processes underpinning neurofeedback could be a key element to develop the use of this technique in clinical practice.

Epileptic seizures can be anticipated by non-linear analysis.

Epileptic seizures are a principal brain dysfunction with important public health implications, as they affect 0.8% of humans. Many of these patients (20%) are resistant to treatment with drugs. The ability to anticipate the onset of seizures in such cases would permit clinical interventions. The view of chronic focal epilepsy now is that abnormally discharging neurons act as pacemakers to recruit and entrain other normal neurons by loss of inhibition and synchronization into a critical mass. Thus, preictal changes should be detectable during the stages of recruitment. Traditional signal analyses, such as the count of focal spike density, the frequency coherence or spectral analyses are not reliable predictors. Non-linear indicators may undergo consistent changes around seizure onset. Our objective was to follow the transition into seizure by reconstructing intracranial recordings in implanted patients as trajectories in a phase space and then introduce non-linear indicators to characterize them. These indicators take into account the extended spatio-temporal nature of the epileptic recruitment processes and the corresponding physiological events governed by short-term causalities in the time series. We demonstrate that in most cases (17 of 19), seizure onset could be anticipated well in advance (between 2-6 minutes beforehand), and that all subjects seemed to share a similar 'route' towards seizure.

[Seizure prediction: from myth to reality]. / Prédiction des crises d'épilepsie: du mythe à la réalité.

INTRODUCTION: Clinical, metabolic and electrophysiologic studies suggest the existence of a preictal state, a transition between the interictal state and seizure. STATE OF THE ART: Analysis of the intracranial EEG by mathematical methods shows changes of the brain dynamics several minutes before the occurrence of partial seizures. These modifications can be widespread and not restricted to the epileptogenic focus, which would explain why they can also be detected from scalp EEG. Several scenarios could underlie the preictal state: a progressive recruitment of neurons or a facilitating state with a high probability of seizure occurrence. Because of the high rate of false predictions, no satisfactory method for seizure prediction has been currently proposed. PERSPECTIVES: A European multicenter study (Evolving platform for improving living expectation of patients suffering from IctAl events [EPILEPSIAE]) is currently evaluating a combination of 44 methods applied for EEG and ECG analysis on long-term recordings obtained from a large multicenter database (www.epilepsiae.eu). CONCLUSION: Combining analyses of multi-level signals including intracranial EEG and microelectrodes, scalp EEG and in vitro electrophysiological studies of post-operative tissues should help clarify brain dynamics during the pre-ictal state.

Loss of phase synchrony in an animal model of partial status epilepticus.

Interrupting a focal, chronic infusion of GABA to the rat motor cortex initiates the progressive emergence of a sustained spiking electroencephalographic (EEG) activity, associated with myoclonic jerks of the corresponding body territory. This activity is maintained over several hours, has an average frequency of 1.5 Hz, is localized to the infusion site and never generalizes. The GABA withdrawal syndrome (GWS) has therefore features of partial status epilepticus. Changes in EEG signals associated with the GWS were studied in freely moving rats by measuring the phase synchrony between bilateral epidural records from the neocortex. Our results showed (i) epileptic activity was associated with a striking decrease in phase synchrony between all pairs of electrodes including the focus, predominantly in the 1-6 Hz frequency range. There was a mean decrease of 75.34+/-5.26% in phase synchrony levels between the period before GABA interruption and the period after epileptic activity appeared. (ii) This reduction in synchrony contrasted with an increase of power spectral density in the corresponding EEG channels over the same 1-6 Hz frequency range, (iii) neither changes in synchrony nor in nonlinear dynamics were detected before the first EEG spikes, (iv) systemic injection of ketamine, an antagonist of N-methyl-d-aspartic acid (NMDA) receptors, modified transiently both epileptic activity and the synchrony profile. (v) Spiking activity and synchrony changes were suppressed by reperfusion of GABA. Our data suggest that, during a partial status epilepticus, interactions between the epileptic focus and connected neocortical neuronal populations are dramatically decreased in low frequencies.

Surface and intracranial EEG spike detection based on discrete wavelet decomposition and random forest classification.

Epilepsy is a neurological disorder for which the electroencephalogram (EEG) is the most important diagnostic tool. In particular, this diagnosis heavily depends on the detection of interictal (between seizures) paroxysmal epileptic discharges (IPED) in the EEG. This is a time-consuming task requiring significant training and experience. Automatic detection of these EEG patterns would greatly assist visual inspections of human readers. We present a new method, which allows automatic detection of IPED based on discrete wavelet decomposition and a random forest classifier. The algorithm was trained and cross validated using 17 subjects with scalp EEG and 10 subjects with intracranial EEG. The performance of this method reached 62% recall and 26% precision for surface EEG subjects and 63% recall and 53% precision for intracranial EEG subjects. Thus, the method hereby proposed has great potential for diagnosis support in clinical environments.

Anticipating epileptic seizures in real time by a non-linear analysis of similarity between EEG recordings.

In a previous publication we showed that non-linear analysis can extract spatio-temporal changes of brain electrical activity prior to epileptic seizures. Here we describe a new method to analyze this long-term non-stationarity in the EEG by a measure of dynamical similarity between different parts of the time series. We apply this method to the study of a group of patients with temporal lobe epilepsy recorded intracranially during transitions to seizure. We show that the method, which can be implemented on a personal computer, can track in real time spatio-temporal changes in brain dynamics several minutes prior to seizure.

Temporal patterns in human epileptic activity are modulated by perceptual discriminations.

We studied subdural recordings from a patient with an unusually focal and stable occipito-temporal epileptic discharge under four experimental conditions. The series of time intervals between successive spike discharges displayed a few (3-5) clusters of periodic values representing statistically significant short-term periodicities when tested against surrogate data. This short-term predictability was modulated during the different experimental conditions by periodicity shifts of the order of 15-30 ms. Correspondingly, there was an increased gamma-band (30-70 Hz) coherence between the epileptic focus and surrounding recording sites. We conclude that the focal epileptic activity is part of an extended network of neural activities which exert a fast modulation reflected in changes of transiently periodic activities.

Nonlinear analysis of orthostatic posture in patients with vertigo or balance disorders.

The stabilometry signals involve irregular and unpredictable components. In order to identify the hidden dynamics that underlie the multi-link networks consisted of the multiple sensory systems, motor components and central integration, we applied a nonlinear analysis to these signals. We evaluated the postural control differences between eyes open and closed by means of the dynamical closeness between two states, known as similarity index, for the patients with vestibular disorders. We were able to demonstrate that some patients (eight of 21) showed a difference between the conventional and nonlinear measures. Especially, the similarity index tended to reflect the clinical course of the vestibular compensation and the findings in the patients with benign paroxysmal positional vertigo (BPPV) demonstrated that its vestibular function may include various pathologies besides canalithiasis. These results suggest that nonlinear analysis can elucidate the complex postural control networks and this procedure may also be able to provide the new findings of the stabilometry examinations.

Comparison of Hilbert transform and wavelet methods for the analysis of neuronal synchrony.

The quantification of phase synchrony between neuronal signals is of crucial importance for the study of large-scale interactions in the brain. Two methods have been used to date in neuroscience, based on two distinct approaches which permit a direct estimation of the instantaneous phase of a signal [Phys. Rev. Lett. 81 (1998) 3291; Human Brain Mapping 8 (1999) 194]. The phase is either estimated by using the analytic concept of Hilbert transform or, alternatively, by convolution with a complex wavelet. In both methods the stability of the instantaneous phase over a window of time requires quantification by means of various statistical dependence parameters (standard deviation, Shannon entropy or mutual information). The purpose of this paper is to conduct a direct comparison between these two methods on three signal sets: (1) neural models; (2) intracranial signals from epileptic patients; and (3) scalp EEG recordings. Levels of synchrony that can be considered as reliable are estimated by using the technique of surrogate data. Our results demonstrate that the differences between the methods are minor, and we conclude that they are fundamentally equivalent for the study of neuroelectrical signals. This offers a common language and framework that can be used for future research in the area of synchronization.

Nonlinear interdependencies of EEG signals in human intracranially recorded temporal lobe seizures.

The degree of interdependence between intracranial EEG channels was investigated in four epileptic patients with complex partial seizures of mesial temporal lobe origin. With a new method to characterize nonlinear dynamical interdependence-the mutual nonlinear prediction-we demonstrated here a possibility to quantify, during epileptic seizures, the relationships between EEG signals of electrode contacts in the epileptogenic area. During the interictal period, the degree of nonlinear interdependences were very low or absent. In contrast, it was found that transient patterns of nonlinear interdependences emerge at the initial spread of the seizure, during essential parts of its development, and at seizure end, but the maintenance of these interactions are not observed throughout the seizure activity. These results suggest that the nonlinear associations plays an important role in epileptogenesis, and that the process of neuronal entrainment during seizure onset involves a transient interaction between a distributed network of neuronal aggregates, but the maintenance of this interaction is not required for sustained seizure activity. Furthermore, this technique can describe properly the spatio-temporal organisation of the seizures of medio-temporal lobe origin and could become a very useful tool to aid the localization of the epileptogenic regions at the origin of epileptic seizures and their pathways of propagation.

Characterizing neurodynamic changes before seizures.

The study of dynamic changes in neural activity preceding epileptic seizure allows the characterization of a preictal state several minutes before seizure onset. This opens up new perspectives for studying the mechanisms of epileptogenesis as well as for possible therapeutic interventions, which represent a major breakthrough. In this review the authors present and discuss the results from their group in this domain using nonlinear analysis of brain signals, as well as the limitations of this topic and current questions.

[Interactions between the epileptic network and brain function: an approach by nonlinear analysis of intracranial EEG]. / Interactions entre réseau épileptique et fonctionnement cérébral: approache par analyse non linéaire de l'EEG intracrânien.

Recent advances in the non-linear dynamics analysis have made it possible to identify hidden recurrences in EEG signals that could be missed by more traditional linear techniques such as power spectrum or coherence analysis. This is particularly true for epileptic EEG recordings either in animals or in humans as epileptic phenomena are usually concomitant with the emergence a strong non-linear EEG behavior. Non-linear dynamical analysis techniques quantify the relations between EEG signals. The literature concerning the spatio-temporal characteristics of the epileptic processes during seizures and interictal periods is reviewed. Our attention has been mainly focused on the interdependences between brain structures or on the dynamical changes of one particular brain region during intracranial recordings. These data could explain in part the dysfunctioning of the cerebral cortex induced by epileptic activities and provide an insight into the spatio-temporal organization of the epileptic network. Futhermore, by tracking the time variation of non-linear indices, one can anticipate the occurrence of seizures in temporal lobe epilepsies. All this information could contribute to improve definitions of the epileptogenic zone in partial epilepsy and also open the way to preventive interventions.

Slow modulations of high-frequency activity (40-140-Hz) discriminate preictal changes in human focal epilepsy.

Recent evidence suggests that some seizures are preceded by preictal changes that start from minutes to hours before an ictal event. Nevertheless an adequate statistical evaluation in a large database of continuous multiday recordings is still missing. Here, we investigated the existence of preictal changes in long-term intracranial recordings from 53 patients with intractable partial epilepsy (in total 531 days and 558 clinical seizures). We describe a measure of brain excitability based on the slow modulation of high-frequency gamma activities (40-140 Hz) in ensembles of intracranial contacts. In prospective tests, we found that this index identified preictal changes at levels above chance in 13.2% of the patients (7/53), suggesting that results may be significant for the whole group (p < 0.05). These results provide a demonstration that preictal states can be detected prospectively from EEG data. They advance understanding of the network dynamics leading to seizure and may help develop novel seizure prediction algorithms.

Recording and analysis techniques for high-frequency oscillations.

In recent years, new recording technologies have advanced such that, at high temporal and spatial resolutions, high-frequency oscillations (HFO) can be recorded in human partial epilepsy. However, because of the deluge of multichannel data generated by these experiments, achieving the full potential of parallel neuronal recordings depends on the development of new data mining techniques to extract meaningful information relating to time, frequency and space. Here, we aim to bridge this gap by focusing on up-to-date recording techniques for measurement of HFO and new analysis tools for their quantitative assessment. In particular, we emphasize how these methods can be applied, what property might be inferred from neuronal signals, and potentially productive future directions.

Dynamics of excitable neural networks with heterogeneous connectivity.

A central issue of neuroscience is to understand how neural units integrates internal and external signals to create coherent states. Recently, it has been shown that the sensitivity and dynamic range of neural assemblies are optimal at a critical coupling among its elements. Complex architectures of connections seem to play a constructive role on the reliable coordination of neural units. Here we show that, the synchronizability and sensitivity of excitable neural networks can be tuned by diversity in the connections strengths. We illustrate our findings for weighted networks with regular, random and complex topologies. Additional comparisons of real brain networks support previous studies suggesting that heterogeneity in the connectivity may play a constructive role on information processing. These findings provide insights into the relationship between structure and function of neural circuits.

Probing cortical excitability using cross-frequency coupling in intracranial EEG recordings: a new method for seizure prediction.

The need of a reliable seizure prediction is motivated by the 50 million people in the world suffering from epilepsy, of whom 30% have no control on seizures with current pharmacological treatments. Seizure prediction research holds great promise for such patients, since an effective algorithm will enable the development of a closed-loop system that intervenes before the clinical onset of a seizure. As a step toward practical implementation of this technology, we present a new method based on a measure of brain excitability identified by couplings between low-frequency phases and high-frequency amplitudes of brain oscillations. The proposed method was applied to long-term intracranial recordings of 20 patients with partial epilepsy, for a total of 267 seizures and more than 3400-hour-long interictal activities. We found that our predictor was in 50% of cases better than chance, with an average sensitivity of 98.9% and false prediction rate of 1.84/hour. From these observations, we concluded that our method enables a new quantitative way to identify preictal states with a high risk of seizure generation.

EPILAB: a software package for studies on the prediction of epileptic seizures.

A Matlab®-based software package, EPILAB, was developed for supporting researchers in performing studies on the prediction of epileptic seizures. It provides an intuitive and convenient graphical user interface. Fundamental concepts that are crucial for epileptic seizure prediction studies were implemented. This includes, for example, the development and statistical validation of prediction methodologies in long-term continuous recordings. Seizure prediction is usually based on electroencephalography (EEG) and electrocardiography (ECG) signals. EPILAB is able to process both EEG and ECG data stored in different formats. More than 35 time and frequency domain measures (features) can be extracted based on univariate and multivariate data analysis. These features can be post-processed and used for prediction purposes. The predictions may be conducted based on optimized thresholds or by applying classifications methods such as artificial neural networks, cellular neuronal networks, and support vector machines. EPILAB proved to be an efficient tool for seizure prediction, and aims to be a way to communicate, evaluate, and compare results and data among the seizure prediction community.

A computational environment for long-term multi-feature and multi-algorithm seizure prediction.

The daily life of epilepsy patients is constrained by the possibility of occurrence of seizures. Until now, seizures cannot be predicted with sufficient sensitivity and specificity. Most of the seizure prediction studies have been focused on a small number of patients, and frequently assuming unrealistic hypothesis. This paper adopts the view that for an appropriate development of reliable predictors one should consider long-term recordings and several features and algorithms integrated in one software tool. A computational environment, based on Matlab (®), is presented, aiming to be an innovative tool for seizure prediction. It results from the need of a powerful and flexible tool for long-term EEG/ECG analysis by multiple features and algorithms. After being extracted, features can be subjected to several reduction and selection methods, and then used for prediction. The predictions can be conducted based on optimized thresholds or by applying computational intelligence methods. One important aspect is the integrated evaluation of the seizure prediction characteristic of the developed predictors.

Spatio-temporal characterizations of non-linear changes in intracranial activities prior to human temporal lobe seizures.

Recent studies have shown that non-linear analysis of intracranial activities can detect a 'pre-ictal phase' preceding the epileptic seizure. Nevertheless, the dynamical nature of the underlying neuronal process and the spatial extension of this pre-ictal phase still remain unknown. In this paper, we address these aspects using a new non-linear measure of dynamic similarity between different parts of intracranial recordings of nine patients with medial temporal lobe epilepsy recorded during transitions to seizure. Our results confirm that non-linear changes in neuronal dynamics allow, in most cases (16 out of 17), a seizure anticipation several minutes in advance. Furthermore, we show that the spatial distribution of pre-ictal changes often involves an extended network projecting beyond the limits of the epileptogenic region. Finally, the pre-ictal phase could frequently (13 out of 17) be characterized with a marked shift toward slower frequencies in upper delta or theta frequency range.