EEG based depression detection by machine learning: Does inner or overt speech condition provide better biomarkers when using emotion words as experimental cues?

BACKGROUND: Objective diagnostic approaches need to be tested to enhance the efficacy of depression detection. Non-invasive EEG-based identification represents a promising area. AIMS: The present EEG study addresses two central questions: 1) whether inner or overt speech condition result in higher diagnositc accuracy of depression detection; and 2) does the affective nature of the presented emotion words count in such diagnostic approach. METHODS: A matched case-control sample consisting of 10 depressed subjects and 10 healthy controls was assessed. An EEG headcap containing 64 electrodes measured neural responses to experimental cues presented in the form of 15 different words that belonged to three emotional categories: neutral, positive, and negative. 120 experimental cues was presented for every participant, each containing an "inner speech" and an "overt speech" segment. An EEGNet neural network was utilized. RESULTS: The highest diagnostic accuracy of the EEGNet model was observed in the case of the overt speech condition (i.e. 69.5%), while a an overall subject-wise accuracy of 80% was achieved by the model. Only a negligible difference in diagnostic accuracy could be found between aggregated emotion word categories, with the highest accuracy (i.e. 70.2%) associated with the presentation of positive emotion words. Model decision was primarily influenced by electrodes representing the regions of the left parietal, the left temporal lobe and the middle frontal areas. CONCLUSIONS: While the generalizability of our results is limited by the small sample size and potentially uncontrolled confounders, depression was associated with sensitive and presumably network-like aspects of these brain areas, potentially implying a higher level of emotion regulation that increases primarily in open communication.

Intracortical mechanisms of single pulse electrical stimulation (SPES) evoked excitations and inhibitions in humans.

Cortico-cortical evoked potentials (CCEPs) elicited by single-pulse electric stimulation (SPES) are widely used to assess effective connectivity between cortical areas and are also implemented in the presurgical evaluation of epileptic patients. Nevertheless, the cortical generators underlying the various components of CCEPs in humans have not yet been elucidated. Our aim was to describe the laminar pattern arising under SPES evoked CCEP components (P1, N1, P2, N2, P3) and to evaluate the similarities between N2 and the downstate of sleep slow waves. We used intra-cortical laminar microelectrodes (LMEs) to record CCEPs evoked by 10 mA bipolar 0.5 Hz electric pulses in seven patients with medically intractable epilepsy implanted with subdural grids. Based on the laminar profile of CCEPs, the latency of components is not layer-dependent, however their rate of appearance varies across cortical depth and stimulation distance, while the seizure onset zone does not seem to affect the emergence of components. Early neural excitation primarily engages middle and deep layers, propagating to the superficial layers, followed by mainly superficial inhibition, concluding in a sleep slow wave-like inhibition and excitation sequence.

Differential cortical layer engagement during seizure initiation and spread in humans.

Despite decades of research, we still do not understand how spontaneous human seizures start and spread - especially at the level of neuronal microcircuits. In this study, we used laminar arrays of micro-electrodes to simultaneously record the local field potentials and multi-unit neural activities across the six layers of the neocortex during focal seizures in humans. We found that, within the ictal onset zone, the discharges generated during a seizure consisted of current sinks and sources only within the infra-granular and granular layers. Outside of the seizure onset zone, ictal discharges reflected current flow in the supra-granular layers. Interestingly, these patterns of current flow evolved during the course of the seizure - especially outside the seizure onset zone where superficial sinks and sources extended into the deeper layers. Based on these observations, a framework describing cortical-cortical dynamics of seizures is proposed with implications for seizure localization, surgical targeting, and neuromodulation techniques to block the generation and propagation of seizures.

Epileptiform discharges in the anterior thalamus of epilepsy patients.

Anterior thalamus (ANT) deep-brain stimulation (DBS) is an approved therapy for drug resistant epilepsy. We aimed to identify interictal epileptiform discharges (IED) in the ANT and to investigate their relationship with surface IEDs. Fifteen patients were monitored for two consecutive nights with externalized thalamic leads to analyze the intrathalamic epileptiform activities (TIED). Forty-six % of all contacts were located within the ANT. We found that all the responders had TIEDs within the ANT, while this held true only for 44% of the non-responders. The overall response rate (RR) at 1-year follow-up was 40%, while it was 44% in bilateral ANT hit patients and 45% in epileptic focus side hit. However, in case of TIEDs present in the focus side the RR reached as high as 71%. TIED activity may prove the pathophysiological connection to the seizure focus, and stimulation of this area might have a better suppressing effect on seizures.

Grading system for assessing the confidence in the epileptogenic zone reported in published studies: A Delphi consensus study.

OBJECTIVE: This study was undertaken to develop a standardized grading system based on expert consensus for evaluating the level of confidence in the localization of the epileptogenic zone (EZ) as reported in published studies, to harmonize and facilitate systematic reviews in the field of epilepsy surgery. METHODS: We conducted a Delphi study involving 22 experts from 18 countries, who were asked to rate their level of confidence in the localization of the EZ for various theoretical clinical scenarios, using different scales. Information provided in these scenarios included one or several of the following data: magnetic resonance imaging (MRI) findings, invasive electroencephalography summary, and postoperative seizure outcome. RESULTS: The first explorative phase showed an overall interrater agreement of .347, pointing to large heterogeneity among experts' assessments, with only 17% of the 42 proposed scenarios associated with a substantial level of agreement. A majority showed preferences for the simpler scale and single-item scenarios. The successive Delphi voting phases resulted in a majority consensus across experts, with more than two thirds of respondents agreeing on the rating of each of the tested single-item scenarios. High or very high levels of confidence were ascribed to patients with either an Engel class I or class IA postoperative seizure outcome, a well-delineated EZ according to all available invasive EEG (iEEG) data, or a well-delineated focal epileptogenic lesion on MRI. MRI signs of hippocampal sclerosis or atrophy were associated with a moderate level of confidence, whereas a low level was ascribed to other MRI findings, a poorly delineated EZ according to iEEG data, or an Engel class II-IV postoperative seizure outcome. SIGNIFICANCE: The proposed grading system, based on an expert consensus, provides a simple framework to rate the level of confidence in the EZ reported in published studies in a structured and harmonized way, offering an opportunity to facilitate and increase the quality of systematic reviews and guidelines in the field of epilepsy surgery.

Temporal association between sleep spindles and ripples in the human anterior and mediodorsal thalamus.

Sleep spindles are major oscillatory components of Non-Rapid Eye Movement (NREM) sleep, reflecting hyperpolarization-rebound sequences of thalamocortical neurons. Reports suggest a link between sleep spindles and several forms of high-frequency oscillations which are considered as expressions of pathological off-line neural plasticity in the central nervous system. Here we investigated the relationship between thalamic sleep spindles and ripples in the anterior and mediodorsal nuclei (ANT and MD) of epilepsy patients. Whole-night LFP from the ANT and MD were co-registered with scalp EEG/polysomnography by using externalized leads in 15 epilepsy patients undergoing a Deep Brain Stimulation protocol. Slow (~12 Hz) and fast (~14 Hz) sleep spindles were present in the human ANT and MD and roughly, 20% of them were associated with ripples. Ripple-associated thalamic sleep spindles were characterized by longer duration and exceeded pure spindles in terms of spindle power as indicated by time-frequency analysis. Furthermore, ripple amplitude was modulated by the phase of sleep spindles within both thalamic nuclei. No signs of pathological processes were correlated with measures of ripple and spindle association, furthermore, the density of ripple-associated sleep spindles in the ANT showed a positive correlation with verbal comprehension. Our findings indicate the involvement of the human thalamus in coalescent spindle-ripple oscillations of NREM sleep.

Prediction tools and risk stratification in epilepsy surgery.

OBJECTIVE: This study was undertaken to conduct external validation of previously published epilepsy surgery prediction tools using a large independent multicenter dataset and to assess whether these tools can stratify patients for being operated on and for becoming free of disabling seizures (International League Against Epilepsy stage 1 and 2). METHODS: We analyzed a dataset of 1562 patients, not used for tool development. We applied two scales: Epilepsy Surgery Grading Scale (ESGS) and Seizure Freedom Score (SFS); and two versions of Epilepsy Surgery Nomogram (ESN): the original version and the modified version, which included electroencephalographic data. For the ESNs, we used calibration curves and concordance indexes. We stratified the patients into three tiers for assessing the chances of attaining freedom from disabling seizures after surgery: high (ESGS = 1, SFS = 3-4, ESNs > 70%), moderate (ESGS = 2, SFS = 2, ESNs = 40%-70%), and low (ESGS = 2, SFS = 0-1, ESNs < 40%). We compared the three tiers as stratified by these tools, concerning the proportion of patients who were operated on, and for the proportion of patients who became free of disabling seizures. RESULTS: The concordance indexes for the various versions of the nomograms were between .56 and .69. Both scales (ESGS, SFS) and nomograms accurately stratified the patients for becoming free of disabling seizures, with significant differences among the three tiers (p < .05). In addition, ESGS and the modified ESN accurately stratified the patients for having been offered surgery, with significant difference among the three tiers (p < .05). SIGNIFICANCE: ESGS and the modified ESN (at thresholds of 40% and 70%) stratify patients undergoing presurgical evaluation into three tiers, with high, moderate, and low chance for favorable outcome, with significant differences between the groups concerning having surgery and becoming free of disabling seizures. Stratifying patients for epilepsy surgery has the potential to help select the optimal candidates in underprivileged areas and better allocate resources in developed countries.

Synaptic alterations and neuronal firing in human epileptic neocortical excitatory networks.

Epilepsy is a prevalent neurological condition, with underlying neuronal mechanisms involving hyperexcitability and hypersynchrony. Imbalance between excitatory and inhibitory circuits, as well as histological reorganization are relatively well-documented in animal models or even in the human hippocampus, but less is known about human neocortical epileptic activity. Our knowledge about changes in the excitatory signaling is especially scarce, compared to that about the inhibitory cell population. This study investigated the firing properties of single neurons in the human neocortex in vitro, during pharmacological blockade of glutamate receptors, and additionally evaluated anatomical changes in the excitatory circuit in tissue samples from epileptic and non-epileptic patients. Both epileptic and non-epileptic tissues exhibited spontaneous population activity (SPA), NMDA receptor antagonization reduced SPA recurrence only in epileptic tissue, whereas further blockade of AMPA/kainate receptors reversibly abolished SPA emergence regardless of epilepsy. Firing rates did not significantly change in excitatory principal cells and inhibitory interneurons during pharmacological experiments. Granular layer (L4) neurons showed an increased firing rate in epileptic compared to non-epileptic tissue. The burstiness of neurons remained unchanged, except for that of inhibitory cells in epileptic recordings, which decreased during blockade of glutamate receptors. Crosscorrelograms computed from single neuron discharge revealed both mono- and polysynaptic connections, particularly involving intrinsically bursting principal cells. Histological investigations found similar densities of SMI-32-immunopositive long-range projecting pyramidal cells in both groups, and shorter excitatory synaptic active zones with a higher proportion of perforated synapses in the epileptic group. These findings provide insights into epileptic modifications from the perspective of the excitatory system and highlight discrete alterations in firing patterns and synaptic structure. Our data suggest that NMDA-dependent glutamatergic signaling, as well as the excitatory synaptic machinery are perturbed in epilepsy, which might contribute to epileptic activity in the human neocortex.

The role of superficial and deep layers in the generation of high frequency oscillations and interictal epileptiform discharges in the human cortex.

Describing intracortical laminar organization of interictal epileptiform discharges (IED) and high frequency oscillations (HFOs), also known as ripples. Defining the frequency limits of slow and fast ripples. We recorded potential gradients with laminar multielectrode arrays (LME) for current source density (CSD) and multi-unit activity (MUA) analysis of interictal epileptiform discharges IEDs and HFOs in the neocortex and mesial temporal lobe of focal epilepsy patients. IEDs were observed in 20/29, while ripples only in 9/29 patients. Ripples were all detected within the seizure onset zone (SOZ). Compared to hippocampal HFOs, neocortical ripples proved to be longer, lower in frequency and amplitude, and presented non-uniform cycles. A subset of ripples (≈ 50%) co-occurred with IEDs, while IEDs were shown to contain variable high-frequency activity, even below HFO detection threshold. The limit between slow and fast ripples was defined at 150 Hz, while IEDs' high frequency components form clusters separated at 185 Hz. CSD analysis of IEDs and ripples revealed an alternating sink-source pair in the supragranular cortical layers, although fast ripple CSD appeared lower and engaged a wider cortical domain than slow ripples MUA analysis suggested a possible role of infragranularly located neural populations in ripple and IED generation. Laminar distribution of peak frequencies derived from HFOs and IEDs, respectively, showed that supragranular layers were dominated by slower (< 150 Hz) components. Our findings suggest that cortical slow ripples are generated primarily in upper layers while fast ripples and associated MUA in deeper layers. The dissociation of macro- and microdomains suggests that microelectrode recordings may be more selective for SOZ-linked ripples. We found a complex interplay between neural activity in the neocortical laminae during ripple and IED formation. We observed a potential leading role of cortical neurons in deeper layers, suggesting a refined utilization of LMEs in SOZ localization.

Deep Brain Stimulation of the Anterior Nucleus of the Thalamus in Drug-Resistant Epilepsy in the MORE Multicenter Patient Registry.

BACKGROUND AND OBJECTIVES: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. METHODS: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. RESULTS: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. DISCUSSION: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy. TRIAL REGISTRATION INFORMATION: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012.

Effects of anterior thalamic nucleus DBS on interictal heart rate variability in patients with refractory epilepsy.

OBJECTIVE: Heart rate variability (HRV) changes were investigated by several studies after resective epilepsy surgery/vagus nerve stimulation. We examined anterior thalamic nucleus (ANT)-deep brain stimulation (DBS) effects on HRV parameters. METHODS: We retrospectively analyzed 30 drug-resistant epilepsy patients' medical record data and collected electrocardiographic epochs recorded during video- electroencephalography monitoring sessions while awake and during N1- or N2-stage sleep pre-DBS implantation surgery, post-surgery but pre-stimulation, and after stimulation began. RESULTS: The mean square root of the mean squared differences between successive RR intervals and RR interval standard deviation values differed significantly (p < 0.05) among time-points, showing increased HRV post-surgery. High (0.15-0.4 Hz) and very low frequency (<0.04 Hz) increased, while low frequency (0.04-0.15 Hz) and the LF/HF ratio while awake decreased, suggesting improved autonomic regulation post-surgery. Change of effect size was larger in patients where both activated contacts were located in the ANT than in those where only one or none of the contacts hit the ANT. CONCLUSIONS: In patients with drug-resistant epilepsy, ANT-DBS might positively influence autonomic regulation, as reflected by increased HRV. SIGNIFICANCE: To gain a more comprehensive outcome estimation after DBS implantation, we suggest including HRV measures with seizure count in the post-surgery follow-up protocol.

The sleep EEG envelope is a novel, neuronal firing-based human biomarker.

Sleep EEG reflects voltage differences relative to a reference, while its spectrum reflects its composition of various frequencies. In contrast, the envelope of the sleep EEG reflects the instantaneous amplitude of oscillations, while its spectrum reflects the rhythmicity of the occurrence of these oscillations. The sleep EEG spectrum is known to relate to demographic, psychological and clinical characteristics, but the envelope spectrum has been rarely studied. In study 1, we demonstrate in human invasive data from cortex-penetrating microelectrodes and subdural grids that the sleep EEG envelope spectrum reflects neuronal firing. In study 2, we demonstrate that the scalp EEG envelope spectrum is stable within individuals. A multivariate learning algorithm could predict age (r = 0.6) and sex (r = 0.5) from the EEG envelope spectrum. With age, oscillations shifted from a 4-5 s rhythm to faster rhythms. Our results demonstrate that the sleep envelope spectrum is a promising biomarker of demographic and disease-related phenotypes.

Role of anterior thalamic circuitry during sleep.

Increased attention has been paid to the structure and function of anterior nucleus of the thalamus (ANT), since deep brain stimulation (DBS) treatment for epilepsy launched a decade ago. The efficacy of the treatment on seizure count varies patient from patient and we have limited information on the predictors of better outcomes. While the thalamus is considered the key brain region responsible for maintaining sleep, ANT was traditionally not involved in this function. Recent experimental and human data point to a possible role of ANT in sleep processes, although the underlying mechanisms are still ambiguous. Beside evaluating the current knowledge on sleep disturbances experienced during ANT-DBS treatment, the search for valid biomarkers primarily resides on a better understanding of sleep circuits implicating ANT and its subnuclei. Hypothetically better selectivity within the target may increase seizure outcomes and reduce psychiatric and cognitive side effects. Hence, the main scope of this review is to summarize the evidence on the activity measured in the ANT during non-REM and REM sleep. Furthermore, we aim to find shared properties of sleep processes and ANT-related functions examined more thoroughly during wakefulness, such as selective attention and memory.

Prolongation of cortical sleep spindles during hippocampal interictal epileptiform discharges in epilepsy patients.

OBJECTIVE: Memory deficits are frequent among patients with epilepsies affecting the temporal lobe. Hippocampal interictal epileptic discharges (hIEDs), the presumed epileptic exaggeration of sharp wave-ripples (SWRs), are known to contribute to memory dysfunction, but the potential underlying mechanism is unknown. The precise temporal coordination between hippocampal SWRs and corticothalamic spindles during sleep is critical for memory consolidation. Moreover, previous investigation indicated that hIEDs induce neocortical spindlelike oscillation. In the present study, we aimed to assess the influence of hIEDs on neocortical spindles. METHODS: We analyzed the spindle characteristics (duration, amplitude, frequency) of 21 epilepsy patients implanted with foramen ovale (FO) electrodes during a whole night sleep. Scalp sleep spindles were categorized based on their temporal relationship to hIEDs detected on the FO electrodes. Three groups were created: (1) spindles coinciding with hIEDs, (2) spindles "induced" by hIEDs, and (3) spindles without hIED co-occurrence. RESULTS: We found that spindles co-occurring with hIEDs had altered characteristics in all measured properties, lasted longer by 126 ± 48 ms (mean ± SD), and had higher amplitude by 3.4 ± 3.2 µV, and their frequency range shifted toward the higher frequencies within the 13-15-Hz range. Also, hIED-induced spindles had identical oscillatory properties to spindles without any temporal relationships with hIEDs. In more than half of our subjects, clear temporal coherence was revealed between hIEDs and spindles, but the direction of the coupling was patient-specific. SIGNIFICANCE: We investigated the effect of hippocampal IEDs on neocortical spindle activity and found spindle alterations in cases of spindle-hIED co-occurrence, but not in cases of hIED-initiated spindles. We propose that this is a marker of a pathologic process, where IEDs may have direct effect on spindle generation. It could mark a potential mechanism whereby IEDs disrupt memory processes, and also provide a potential therapeutic target to treat memory disturbances in epilepsy.

PET/MRI in the Presurgical Evaluation of Patients with Epilepsy: A Concordance Analysis.

The aim of our prospective study was to evaluate the clinical impact of hybrid [18F]-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging ([18F]-FDG PET/MRI) on the decision workflow of epileptic patients with discordant electroclinical and MRI data. A novel mathematical model was introduced for a clinical concordance calculation supporting the classification of our patients by subgroups of clinical decisions. Fifty-nine epileptic patients with discordant clinical and diagnostic results or MRI negativity were included in this study. The diagnostic value of the PET/MRI was compared to other modalities of presurgical evaluation (e.g., electroclinical data, PET, and MRI). The results of the population-level statistical analysis of the introduced data fusion technique and concordance analysis demonstrated that this model could be the basis for the development of a more accurate clinical decision support parameter in the future. Therefore, making the establishment of "invasive" (operable and implantable) and "not eligible for any further invasive procedures" groups could be much more exact. Our results confirmed the relevance of PET/MRI with the diagnostic algorithm of presurgical evaluation. The introduction of a concordance analysis could be of high importance in clinical and surgical decision-making in the management of epileptic patients. Our study corroborated previous findings regarding the advantages of hybrid PET/MRI technology over MRI and electroclinical data.

Thalamic activity during scalp slow waves in humans.

Slow waves are major pacemakers of NREM sleep oscillations. While slow waves themselves are mainly generated by cortical neurons, it is not clear what role thalamic activity plays in the generation of some oscillations grouped by slow waves, and to what extent thalamic activity during slow waves is itself driven by corticothalamic inputs. To address this question, we simultaneously recorded both scalp EEG and local field potentials from six thalamic nuclei (bilateral anterior, mediodorsal and ventral anterior) in fifteen epileptic patients (age-range: 17-64 years, 7 females) undergoing Deep Brain Stimulation Protocol and assessed the temporal evolution of thalamic activity relative to scalp slow waves using time-frequency analysis. We found that thalamic activity in all six nuclei during scalp slow waves is highly similar to what is observed on the scalp itself. Slow wave downstates are characterized by delta, theta and alpha activity and followed by beta, high sigma and low sigma activity during subsequent upstates. Gamma activity in the thalamus is not significantly grouped by slow waves. Theta and alpha activity appeared first on the scalp, but sigma activity appeared first in the thalamus. These effects were largely independent from the scalp region in which SWs were detected and the precise identity of thalamic nuclei. Our results suggest that while small thalamocortical neuron assemblies may initiate cortical oscillations, especially in the sleep spindle range, the large-scale neuronal activity in the thalamus which is detected by field potentials is principally driven by global cortical activity, and thus it is highly similar to what is observed on the scalp.

Reorganization of Parvalbumin Immunopositive Perisomatic Innervation of Principal Cells in Focal Cortical Dysplasia Type IIB in Human Epileptic Patients.

Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy. As several studies have revealed, the abnormal functioning of the perisomatic inhibitory system may play a role in the onset of seizures. Therefore, we wanted to investigate whether changes of perisomatic inhibitory inputs are present in FCD. Thus, the input properties of abnormal giant- and control-like principal cells were examined in FCD type IIB patients. Surgical samples were compared to controls from the same cortical regions with short postmortem intervals. For the study, six subjects were selected/each group. The perisomatic inhibitory terminals were quantified in parvalbumin and neuronal nuclei double immunostained sections using a confocal fluorescent microscope. The perisomatic input of giant neurons was extremely abundant, whereas control-like cells of the same samples had sparse inputs. A comparison of pooled data shows that the number of parvalbumin-immunopositive perisomatic terminals contacting principal cells was significantly larger in epileptic cases. The analysis showed some heterogeneity among epileptic samples. However, five out of six cases had significantly increased perisomatic input. Parameters of the control cells were homogenous. The reorganization of the perisomatic inhibitory system may increase the probability of seizure activity and might be a general mechanism of abnormal network activity.

Bursting of excitatory cells is linked to interictal epileptic discharge generation in humans.

Knowledge about the activity of single neurons is essential in understanding the mechanisms of synchrony generation, and particularly interesting if related to pathological conditions. The generation of interictal spikes-the hypersynchronous events between seizures-is linked to hyperexcitability and to bursting behaviour of neurons in animal models. To explore its cellular mechanisms in humans we investigated the activity of clustered single neurons in a human in vitro model generating both physiological and epileptiform synchronous events. We show that non-epileptic synchronous events resulted from the finely balanced firing of excitatory and inhibitory cells, which was shifted towards an enhanced excitability in epileptic tissue. In contrast, interictal-like spikes were characterised by an asymmetric overall neuronal discharge initiated by excitatory neurons with the presumptive leading role of bursting pyramidal cells, and possibly terminated by inhibitory interneurons. We found that the overall burstiness of human neocortical neurons is not necessarily related to epilepsy, but the bursting behaviour of excitatory cells comprising both intrinsic and synaptically driven bursting is clearly linked to the generation of epileptiform synchrony.

Manifold-adaptive dimension estimation revisited.

Data dimensionality informs us about data complexity and sets limit on the structure of successful signal processing pipelines. In this work we revisit and improve the manifold adaptive Farahmand-Szepesvári-Audibert (FSA) dimension estimator, making it one of the best nearest neighbor-based dimension estimators available. We compute the probability density function of local FSA estimates, if the local manifold density is uniform. Based on the probability density function, we propose to use the median of local estimates as a basic global measure of intrinsic dimensionality, and we demonstrate the advantages of this asymptotically unbiased estimator over the previously proposed statistics: the mode and the mean. Additionally, from the probability density function, we derive the maximum likelihood formula for global intrinsic dimensionality, if i.i.d. holds. We tackle edge and finite-sample effects with an exponential correction formula, calibrated on hypercube datasets. We compare the performance of the corrected median-FSA estimator with kNN estimators: maximum likelihood (Levina-Bickel), the 2NN and two implementations of DANCo (R and MATLAB). We show that corrected median-FSA estimator beats the maximum likelihood estimator and it is on equal footing with DANCo for standard synthetic benchmarks according to mean percentage error and error rate metrics. With the median-FSA algorithm, we reveal diverse changes in the neural dynamics while resting state and during epileptic seizures. We identify brain areas with lower-dimensional dynamics that are possible causal sources and candidates for being seizure onset zones.