Sleep modulates effective connectivity: A study using intracranial stimulation and recording.

OBJECTIVE: Sleep is an active process with an important role in memory. Epilepsy patients often display a disturbed sleep architecture, with consequences on cognition. We aimed to investigate the effect of sleep on cortical networks' organization. METHODS: We analyzed cortico-cortical evoked responses elicited by single pulse electrical stimulation (SPES) using intracranial depth electrodes in 25 patients with drug-resistant focal epilepsy explored using stereo-EEG. We applied the SPES protocol during wakefulness and NREM - N2 sleep. We analyzed 31,710 significant responses elicited by 799 stimulations covering most brain structures, epileptogenic or non-epileptogenic. We analyzed effective connectivity between structures using a graph-theory approach. RESULTS: Sleep increases excitability in the brain, regardless of epileptogenicity. Local and distant connections are differently modulated by sleep, depending on the tissue epileptogenicity. In non-epileptogenic areas, frontal lobe connectivity is enhanced during sleep. There is increased connectivity between the hippocampus and temporal neocortex, while perisylvian structures are disconnected from the temporal lobe. In epileptogenic areas, we found a clear interhemispheric difference, with decreased connectivity in the right hemisphere during sleep. CONCLUSIONS: Sleep modulates brain excitability and reconfigures functional brain networks, depending on tissue epileptogenicity. SIGNIFICANCE: We found specific patterns of information flow during sleep in physiologic and pathologic structures, with possible implications for cognition.

Can histologically normal epileptogenic zone share common electrophysiological phenotypes with focal cortical dysplasia? SEEG-based study in MRI-negative epileptic patients.

OBJECTIVE: We aimed to assess stereoelectroencephalography (SEEG) seizure-onset and interictal patterns associated with MRI-negative epilepsy and investigate their possible links with histology, extent of the epileptogenic zone (EZ) and surgical outcome. METHODS: We retrospectively analysed a cohort of 59 consecutive MRI-negative surgical candidates, who underwent SEEG recordings followed by cortectomy between 2000 and 2016. RESULTS: Most of the eight distinct seizure-onset patterns could be encountered both in confirmed focal cortical dysplasia (FCD) and in histologically non-specific or normal cases. We found strong correlation (p = 0.008) between seizure-onset pattern and histology for: (1) slow-wave/DC-shift prior to low voltage fast activity (LVFA), associated with normal/non-specific histology, and (2) bursts of polyspikes prior to LVFA, exclusively observed in FCD. Three interictal patterns were identified: periodic slow-wave/gamma burst, sub-continuous rhythmic spiking and irregular spikes. Both "periodic" patterns were more frequent in but not specific to FCD. Surgical outcome depended on the EZ complete removal, regardless electrophysiological features. CONCLUSIONS: Histologically normal and FCD-associated epileptogenic zones share distinct interictal and ictal electrophysiological phenotypes, with common patterns between FCD subtypes and between dysplastic and apparently normal brain. SIGNIFICANCE: Some specific seizure-onset patterns seem to be predictive of the underlying histology and may help to detect an MRI-invisible FCD.

Illusory own body perceptions mapped in the cingulate cortex-An intracranial stimulation study.

Body awareness is the result of sensory integration in the posterior parietal cortex; however, other brain structures are part of this process. Our goal is to determine how the cingulate cortex is involved in the representation of our body. We retrospectively selected patients with drug-resistant epilepsy, explored by stereo-electroencephalography, that had the cingulate cortex sampled outside the epileptogenic zone. The clinical effects of high-frequency electrical stimulation were reviewed and only those sites that elicited changes related to body perception were included. Connectivity of the cingulate cortex and other cortical structures was assessed using the h2 coefficient, following a nonlinear regression analysis of the broadband EEG signal. Poststimulation changes in connectivity were compared between two sets of stimulations eliciting or not eliciting symptoms related to body awareness (interest and control groups). We included 17 stimulations from 12 patients that reported different types of body perception changes such as sensation of being pushed toward right/left/up, one limb becoming heavier/lighter, illusory sensation of movement, sensation of pressure, sensation of floating or detachment of one hemi-body. High-frequency stimulation in the cingulate cortex (1 anterior, 15 middle, 1 posterior part) elicits body perception changes, associated with a decreased connectivity of the dominant posterior insula and increased coupling between other structures, located particularly in the nondominant hemisphere.

Functional mapping and effective connectivity of the human operculum.

The operculum, defined as the cortex adjacent to the insula, is a large structure encompassing three lobes, with a recognized role in a variety of neurologic and psychiatric conditions. Its complex functions include sensory, motor, autonomic and cognitive processing. In humans, these are extended with the addition of language. These functions are implemented by highly specialized neuronal populations and their widespread connections, which our study aims at mapping in detail. We studied a group of 31 patients that were explored with intracranial electrodes during the pre-surgical workup for drug-resistant epilepsy. We have selected the subset of contacts implanted in non-epileptogenic opercular cortex and we analyzed the neurophysiological and behavioral responses to direct electrical stimulation. The functional mapping was performed by applying 1 Hz and 50 Hz electrical stimulation on 252 contact pairs and recording the threshold for evoking clinical effects. The effective connectivity was assessed using cortico-cortical evoked potentials elicited by single-pulse electrical stimulation in a subset of 19 patients. The locations of the effects grouped in twelve distinct semiological classes were analyzed. The most frequent effects evoked by stimulation of the frontal operculum were language related (29%). The Rolandic area produced most often oropharyngeal symptoms (47%), the parietal operculum produced somatosensory effects (67%), while the temporal evoked auditory (58%) semiology. The connectivity pattern was complex, with these structures having widespread ipsilateral and contralateral projections. The local connections between the opercular subregions and with the insula, as well as with more distant areas like the cingulate gyrus, were distinguished by strength and between-subjects consistency. In conclusion, we demonstrate specific opercular functionality, distinct from the one of the insular cortex. The study is complemented by a literature review on the opercular functional connectome in human and non-human primates.

High frequency spectral changes induced by single-pulse electric stimulation: Comparison between physiologic and pathologic networks.

OBJECTIVE: To investigate functional coupling between brain networks using spectral changes induced by single-pulse electric stimulation (SPES). METHOD: We analyzed 20 patients with focal epilepsy, implanted with depth electrodes. SPES was applied to each pair of adjacent contacts, and responses were recorded from all other contacts. The mean response amplitude value was quantified in three time-periods after stimulation (10-60, 60-255, 255-500ms) for three frequency-ranges (Gamma, Ripples, Fast-Ripples), and compared to baseline. A total of 30,755 responses were analyzed, taking into consideration three dichotomous pairs: stimulating in primary sensory areas (S1-V1) vs. outside them, to test the interaction in physiologic networks; stimulating in seizure onset zone (SOZ) vs. non-SOZ, to test pathologic interactions; recording in default mode network (DMN) vs. non-DMN. RESULTS: Overall, we observed an early excitation (10-60ms) and a delayed inhibition (60-500ms). More specifically, in the delayed period, stimulation in S1-V1 produced a higher gamma-inhibition in the DMN, while stimulation in the SOZ induced a higher inhibition in the epilepsy-related higher frequencies (Ripples and Fast-Ripples). CONCLUSION: Physiologic and pathologic interactions can be assessed using spectral changes induced by SPES. SIGNIFICANCE: This is a promising method for connectivity studies in patients with drug-resistant focal epilepsy.

Intrusive Thoughts Elicited by Direct Electrical Stimulation during Stereo-Electroencephalography.

Cortical direct electrical stimulation (DES) is a method of brain mapping used during invasive presurgical evaluation of patients with intractable epilepsy. Intellectual auras like intrusive thoughts, also known as forced thinking (FT), have been reported during frontal seizures. However, there are few reports on FT obtained during DES in frontal cortex. We report three cases in which we obtained intrusive thoughts while stimulating the dorsolateral prefrontal cortex and the white matter in the prefrontal region. In order to highlight the effective connectivity that might explain this clinical response, we have analyzed cortico-cortical potentials evoked by single pulse electrical stimulation.

Stimulation artifact correction method for estimation of early cortico-cortical evoked potentials.

BACKGROUND: Effective connectivity can be explored using direct electrical stimulations in patients suffering from drug-resistant focal epilepsies and investigated with intracranial electrodes. Responses to brief electrical pulses mimic the physiological propagation of signals and manifest as cortico-cortical evoked potentials (CCEP). The first CCEP component is believed to reflect direct connectivity with the stimulated region but the stimulation artifact, a sharp deflection occurring during a few milliseconds, frequently contaminates it. NEW METHOD: In order to recover the characteristics of early CCEP responses, we developed an artifact correction method based on electrical modeling of the electrode-tissue interface. The biophysically motivated artifact templates are then regressed out of the recorded data as in any classical template-matching removal artifact methods. RESULTS: Our approach is able to make the distinction between the physiological responses time-locked to the stimulation pulses and the non-physiological component. We tested the correction on simulated CCEP data in order to quantify its efficiency for different stimulation and recording parameters. We demonstrated the efficiency of the new correction method on simulations of single trial recordings for early responses contaminated with the stimulation artifact. The results highlight the importance of sampling frequency for an accurate analysis of CCEP. We then applied the approach to experimental data. COMPARISON WITH EXISTING METHOD: The model-based template removal was compared to a correction based on the subtraction of the averaged artifact. CONCLUSIONS: This new correction method of stimulation artifact will enable investigators to better analyze early CCEP components and infer direct effective connectivity in future CCEP studies.

A connectomics approach combining structural and effective connectivity assessed by intracranial electrical stimulation.

In the context of the human brain, the term "connectivity" can refer to structural, functional or effective connectivity. Intracranial electrical stimulation is perhaps the most direct way of investigating the effective connectivity. We propose a method of mapping the effective connectivity, revealed by the electrical stimulation of brain structures, over the structural connectome (SC), obtained through diffusion spectrum imaging (DSI), to form a structural-effective connectome (SEC). A number of 24 patients with refractory epilepsy were implanted with depth electrodes for pre-surgical evaluation. Effective connectivity was assessed by analyzing the responses to single pulse electrical stimulation (SPES). Stimulation pulses having variable amplitude were applied to each pair of adjacent contacts and responses evoked by stimulation were recorded from other contacts located in other brain areas. Early responses (10-110 ms) on the stimulation-activated contacts located outside the epileptogenic zone were averaged for each patient, resulting in a patient-level physiological effective connectome (EC). The population level EC is computed by averaging the connections of the individual ECs, on a structure by structure basis. A fiber activation factor is used to weight the number of fibers connecting a pair of structures in the SC by its corresponding normalized EC value. The resulting number of effectively activated fibers describes the directional connection strength between two structures in the SEC. A physiological SEC comprising directional connections between 70 segmented brain areas in both hemispheres, was obtained by inclusion of structures outside the epileptogenic zone only. Over the entire structure set, the Spearman's correlation coefficient ρ between the number of fibers extracted from the DSI Atlas and the normalized RMS responses to SPES was ρ=0.21 (p<0.001), while Kendall's tau coefficients ranged -0.52-0.44 (p<0.05). The physiological structural-effective connectomics approach we have introduced can be applied for the creation of a whole-brain connectivity atlas that can be used as a reference tool for differential analysis of altered versus normal brain connectivity in epileptic patients.

Successful epilepsy surgery in frontal lobe epilepsy with startle seizures: a SEEG study.

Pre-surgical assessment and surgical management of frontal epilepsy with normal MRI is often challenging. We present a case of a 33-year-old, right-handed, educated male. During childhood, his seizures presented with mandibular myoclonus and no particular trigger. As a young adult, he developed seizures with a startle component, triggered by unexpected noises. During his ictal episodes, he felt fear and grimaced with sudden head flexion and tonic axial posturing. Similar seizures also occurred without startle. Neuropsychological assessment showed executive dysfunction and verbal memory deficit. The cerebral MRI was normal. Electro-clinical reasoning, investigations performed, the results obtained and follow-up are discussed in detail. [Published with video sequence].

A phase II trial of gemcitabine and docetaxel in patients with chemotherapy-naive, advanced nonsmall cell lung carcinoma.

BACKGROUND: The goals of the current study were to determine the safety and efficacy of a nonplatinum-containing doublet, gemcitabine and docetaxel, in the treatment of patients with chemotherapy-naive nonsmall cell lung carcinoma (NSCLC). METHODS: Thirty-two patients with advanced, chemotherapy-naive NSCLC were treated with gemcitabine (1000 mg/m(2)) and docetaxel (40 mg/m(2)) administered on Days 1 and 8 every 21 days. All patients were evaluable for toxicity and survival and 27 patients were evaluable for response. RESULTS: This combination was extremely well tolerated with Grade 3 or 4 neutropenia occurring in 6 of 32 patients (19%) (grading was based on the National Cancer Institute Common Toxicity Criteria). There were two episodes of Grade 3 thrombocytopenia and no episodes of Grade 3 or 4 anemia. Grade 3 or 4 nonhematologic toxicities included nausea (occurring in 1 of 32 patients), diarrhea (occurring in 1 of 32 patients), fatigue (occurring in 10 of 32 patients), fluid retention (occurring in 2 of 32 patients), anorexia (occurring in 4 of 32 patients), and transaminitis (occurring in 2 of 32 patients). Six patients experienced Grade 3 pneumonitis that was at least possibly related to the combination of gemcitabine and docetaxel. There was 1 complete response and 7 partial responses for an overall response rate of 30%. The 1-year and median survivals were 35% and 7.9 months, respectively. CONCLUSIONS: In the current study, the regimen of gemcitabine (1000 mg/m(2)) and docetaxel (40 mg/m(2)) administered on Days 1 and 8 every 21 days was well tolerated with manageable hematologic and nonhematologic toxicities. The responses were comparable to those achieved with platinum-based combination chemotherapy and the 2-year survival was an encouraging 19%. These data would support the further study of this nonplatinum doublet in patients with advanced NSCLC.