Detecting directional coupling in the human epileptic brain: Limitations and potential pitfalls

We study directional relationships—in the driver-responder sense—in networks of coupled nonlinear oscillators using a phase modeling approach. Specifically, we focus on the identification of drivers in clusters with varying levels of synchrony, mimicking dynamical interactions between the seizure generating region (epileptic focus) and other brain structures. We demonstrate numerically that such an identification is not always possible in a reliable manner. Using the same analysis techniques as in model systems, we study multichannel electroencephalographic recordings from two patients suffering from focal epilepsy. Our findings demonstrate that—depending on the degree of intracluster synchrony—certain subsystems can spuriously appear to be driving others, which should be taken into account when analyzing field data with unknown underlying dynamics

Internetwork and intranetwork communications during bursting dynamics: Applications to seizure prediction

We use a simple dynamical model of two interacting networks of integrate-and-fire neurons to explain a seemingly paradoxical result observed in epileptic patients indicating that the level of phase synchrony declines below normal levels during the state preceding seizures (preictal state). We model the transition from the seizure free interval (interictal state) to the seizure (ictal state) as a slow increase in the mean depolarization of neurons in a network corresponding to the epileptic focus. We show that the transition from the interictal to preictal and then to the ictal state may be divided into separate dynamical regimes: the formation of slow oscillatory activity due to resonance between the two interacting networks observed during the interictal period, structureless activity during the preictal period when the two networks have different properties, and bursting dynamics driven by the network corresponding to the epileptic focus. Based on this result, we hypothesize that the beginning of the preictal period marks the beginning of the transition of the epileptic network from normal activity toward seizing

Latency and Selectivity of Single Neurons Indicate Hierarchical Processing in the Human Medial Temporal Lobe

Neurons in the temporal lobe of both monkeys and humans show selective responses to classes of visual stimuli and even to specific individuals. In this study, we investigate the latency and selectivity of visually responsive neurons recorded from microelectrodes in the parahippocampal cortex, entorhinal cortex, hippocampus, and amygdala of human subjects during a visual object presentation task. During 96 experimental sessions in 35 subjects, we recorded from a total of 3278 neurons. Of these units, 398 responded selectively to one or more of the presented stimuli. Mean response latencies were substantially larger than those reported in monkeys. We observed a highly significant correlation between the latency and the selectivity of these neurons: the longer the latency the greater the selectivity. Particularly, parahippocampal neurons were found to respond significantly earlier and less selectively than those in the other three regions. Regional analysis showed significant correlations between latency and selectivity within the parahippocampal cortex, entorhinal cortex, and hippocampus, but not within the amygdala. The later and more selective responses tended to be generated by cells with sparse baseline firing rates and vice versa. Our results provide direct evidence for hierarchical processing of sensory information at the interface between the visual pathway and the limbic system, by which increasingly refined and specific representations of stimulus identity are generated over time along the anatomic pathways of the medial temporal lobe

Neural correlates of consciousness

Consciousness is a puzzling, state-dependent property of certain types of complex, biological, adaptive, and highly interconnected systems. A science of consciousness must strive to explain the exact relationship between phenomenal, mental states and brain states. This is the heart of the classical mind-body problem: What is the nature of the relationship between the immaterial, conscious mind and its physical basis in the electrochemical interactions in the body? Brain scientists are exploiting a number of empirical approaches to shed light on the neural basis of consciousness. This article reviews these approaches and summarizes what has been learnt

Independent Delta/Theta Rhythms in the Human Hippocampus and Entorhinal Cortex

Theta oscillations in the medial temporal lobe (MTL) of mammals are involved in various functions such as spatial navigation, sensorimotor integration, and cognitive processing. While the theta rhythm was originally assumed to originate in the medial septum, more recent studies suggest autonomous theta generation in the MTL. Although coherence between entorhinal and hippocampal theta activity has been found to influence memory formation, it remains unclear whether these two structures can generate theta independently. In this study we analyzed intracranial electroencephalographic (EEG) recordings from 22 patients with unilateral hippocampal sclerosis undergoing presurgical evaluation prior to resection of the epileptic focus. Using a wavelet-based, frequency-band-specific measure of phase synchronization, we quantified synchrony between 10 different recording sites along the longitudinal axis of the hippocampal formation in the non-epileptic brain hemisphere. We compared EEG synchrony between adjacent recording sites (i) within the entorhinal cortex, (ii) within the hippocampus, and (iii) between the hippocampus and entorhinal cortex. We observed a significant interregional gap in synchrony for the delta and theta band, indicating the existence of independent delta/theta rhythms in different subregions of the human MTL. The interaction of these rhythms could represent the temporal basis for the information processing required for mnemonic encoding and retrieval

Persistent Single-Neuron Activity during Working Memory in the Human Medial Temporal Lobe

Working memory is an essential component of human cognition. Persistent activity related to working memory has been reported in many brain areas, including the inferior temporal and prefrontal cortex [1; 2; 3; 4; 5; 6; 7 ; 8]. The medial temporal lobe (MTL) contains “concept cells” that respond invariantly to specific individuals or places whether presented as images, text, or speech [9 ; 10]. It is unknown, however, whether the MTL also participates in working memory processes. We thus sought to determine whether human MTL neurons respond to images held in working memory. We recorded from patients with chronically intractable epilepsy as they performed a task that required them to remember three or four sequentially presented pictures across a brief delay. 48% of visually selective neurons continued to carry image-specific information after image offset, but most ceased to encode previously presented images after a subsequent presentation of a different image. However, 8% of visually selective neurons encoded previously presented images during a final maintenance period, despite presentation of further images in the intervening interval. Population activity of stimulus-selective neurons predicted behavioral outcome in terms of correct and incorrect responses. These findings indicate that the MTL is part of a brain-wide network for working memory

Assessing criticality in pre-seizure single-neuron activity of human epileptic cortex

Epileptic seizures are characterized by abnormal and excessive neural activity, where cortical network dynamics seem to become unstable. However, most of the time, during seizure-free periods, cortex of epilepsy patients shows perfectly stable dynamics. This raises the question of how recurring instability can arise in the light of this stable default state. In this work, we examine two potential scenarios of seizure generation: (i) epileptic cortical areas might generally operate closer to instability, which would make epilepsy patients generally more susceptible to seizures, or (ii) epileptic cortical areas might drift systematically towards instability before seizure onset. We analyzed single-unit spike recordings from both the epileptogenic (focal) and the nonfocal cortical hemispheres of 20 epilepsy patients. We quantified the distance to instability in the framework of criticality, using a novel estimator, which enables an unbiased inference from a small set of recorded neurons. Surprisingly, we found no evidence for either scenario: Neither did focal areas generally operate closer to instability, nor were seizures preceded by a drift towards instability. In fact, our results from both pre-seizure and seizure-free intervals suggest that despite epilepsy, human cortex operates in the stable, slightly subcritical regime, just like cortex of other healthy mammalians.Comment: 19 pages, 8 Figure

Independent Delta/Theta Rhythms in the Human Hippocampus and Entorhinal Cortex

Theta oscillations in the medial temporal lobe (MTL) of mammals are involved in various functions such as spatial navigation, sensorimotor integration, and cognitive processing. While the theta rhythm was originally assumed to originate in the medial septum, more recent studies suggest autonomous theta generation in the MTL. Although coherence between entorhinal and hippocampal theta activity has been found to influence memory formation, it remains unclear whether these two structures can generate theta independently. In this study we analyzed intracranial electroencephalographic (EEG) recordings from 22 patients with unilateral hippocampal sclerosis undergoing presurgical evaluation prior to resection of the epileptic focus. Using a wavelet-based, frequency-band-specific measure of phase synchronization, we quantified synchrony between 10 different recording sites along the longitudinal axis of the hippocampal formation in the non-epileptic brain hemisphere. We compared EEG synchrony between adjacent recording sites (i) within the entorhinal cortex, (ii) within the hippocampus, and (iii) between the hippocampus and entorhinal cortex. We observed a significant interregional gap in synchrony for the delta and theta band, indicating the existence of independent delta/theta rhythms in different subregions of the human MTL. The interaction of these rhythms could represent the temporal basis for the information processing required for mnemonic encoding and retrieval

Entropically-driven binding of mithramycin in the minor groove of C/G-rich DNA sequences

Final full-text version available at: http://dx.doi.org/10.1093/nar/gkm037.-- Supplementary Data is available.The antitumour antibiotic mithramycin A (MTA) is a DNA minor-groove binding ligand. It binds to C/G-rich tracts as a dimer that forms in the presence of divalent cations such as Mg2+. Differential scanning calorimetry, UV thermal denaturation, isothermal titration calorimetry and competition dialysis were used, together with computations of the hydrophobic free energy of binding, to determine the thermodynamic profile of MTA binding to DNA. The results were compared to those obtained in parallel using the structurally related mithramycin SK (MSK). The binding of MTA to salmon testes DNA determined by UV melting studies (Kobs = 1.2 (±0.3) x 10^5 M–1) is tighter than that of MSK (2.9 (±1.0) x 10^4 M–1) at 25°C. Competition dialysis studies showed a tighter MTA binding to both salmon testes DNA (42% C + G) and Micrococcus lysodeikticus DNA (72% C + G). The thermodynamic analysis of binding data at 25°C shows that the binding of MTA and MSK to DNA is entropically driven, dominated by the hydrophobic transfer of the antibiotics from solution to the DNA-binding site. Direct molecular recognition between MTA or MSK and DNA through hydrogen bonding and van der Waals contacts may also contribute significantly to complex formation.Supported by a grant from the Spanish Ministry of Education and Science (SAF2005-00551) and the FEDER program of the European Community. This work was carried out within the framework of the Centre de Referencia en Biotecnologia of the Generalitat de Catalunya. Funding to pay the Open Access publication charge was provided by the Ministry of Education and Science and CSIC (Spain).Peer reviewe

Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism

<p>Abstract</p> <p>Background</p> <p>Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death.</p> <p>Methods</p> <p>To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR.</p> <p>Results</p> <p>While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus.</p> <p>Conclusion</p> <p>Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy.</p