Search

Abstract Background 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. Methods 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. Results 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. Conclusion 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.

The epileptogenic network in temporal lobe epilepsy (TLE) contains structures of the primary and secondary olfactory cortex such as the piriform and entorhinal cortex, the amygdala, and the hippocampus. Olfactory auras and olfactory dysfunction are relevant symptoms of TLE. This study aims to characterize olfactory function in TLE using olfactory testing and olfactory functional magnetic resonance imaging (fMRI). We prospectively enrolled 20 individuals with unilateral TLE (age 45 ± 20 years [mean ± SD], 65% female, 90% right-handed) and 20 healthy individuals (age 33 ± 15 years [mean ± SD], 35% female, 90% right-handed). In the TLE group, the presumed seizure onset zone was left-sided in 75%; in 45% of the individuals with TLE limbic encephalitis was the presumed etiology; and 15% of the individuals with TLE reported olfactory auras. Olfactory function was assessed with a Screening Sniffin' Sticks Test (Burkhart, Wedel, Germany) during a pre-assessment. During a pre-testing, all individuals were asked to rate the intensity, valence, familiarity, and associated memory of five different odors (eugenol, vanillin, phenethyl alcohol, decanoic acid, valeric acid) and a control solution. During the fMRI experiment, all individuals repeatedly smelled eugenol (positively valenced odor), valeric acid (negatively valenced odor), and the control solution and were asked to rate odor intensity on a five-point Likert scale. We acquired functional EPI sequences and structural images (T1, T2, FLAIR). Compared to healthy individuals, individuals with TLE rated the presented odors as more neutral (two-sided Mann-Whitney U tests, FDR-p < 0.05) and less familiar (two-sided Mann-Whitney U tests, FDR-p < 0.05). fMRI data analysis revealed a reduced response contrast in secondary olfactory areas (e.g., hippocampus) connected to the limbic system when comparing eugenol and valeric acid in individuals with TLE when compared with healthy individuals. However, no lateralization effect was obtained when calculating a lateralization index by the number of activated voxels in the olfactory system (two-sided Mann-Whitney U test; U = 176.0; p = 0.525). TLE is characterized by olfactory dysfunction and associated with hypoactivation of secondary olfactory structures connected to the limbic system. These findings contribute to our understanding of the pathophysiology of TLE. This study was preregistered on OSF Registries (www.osf.io)., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Olfaction is a fundamental sensory modality that guides animal and human behaviour 1,2 . However, the underlying neural processes of human olfaction are still poorly understood at the fundamental-that is, the single-neuron-level. Here we report recordings of single-neuron activity in the piriform cortex and medial temporal lobe in awake humans performing an odour rating and identification task. We identified odour-modulated neurons within the piriform cortex, amygdala, entorhinal cortex and hippocampus. In each of these regions, neuronal firing accurately encodes odour identity. Notably, repeated odour presentations reduce response firing rates, demonstrating central repetition suppression and habituation. Different medial temporal lobe regions have distinct roles in odour processing, with amygdala neurons encoding subjective odour valence, and hippocampal neurons predicting behavioural odour identification performance. Whereas piriform neurons preferably encode chemical odour identity, hippocampal activity reflects subjective odour perception. Critically, we identify that piriform cortex neurons reliably encode odour-related images, supporting a multimodal role of the human piriform cortex. We also observe marked cross-modal coding of both odours and images, especially in the amygdala and piriform cortex. Moreover, we identify neurons that respond to semantically coherent odour and image information, demonstrating conceptual coding schemes in olfaction. Our results bridge the long-standing gap between animal models and non-invasive human studies and advance our understanding of odour processing in the human brain by identifying neuronal odour-coding principles, regional functional differences and cross-modal integration., (© 2024. The Author(s).)

Our brains create new memories by capturing the 'who/what', 'where' and 'when' of everyday experiences. On a neuronal level, mechanisms facilitating a successful transfer into episodic memory are still unclear. We investigated this by measuring single neuron activity in the human medial temporal lobe during encoding of item-location associations. While previous research has found predictive effects in population activity in human MTL structures, we could attribute such effects to two specialized sub-groups of neurons: concept cells in the hippocampus, amygdala and entorhinal cortex (EC), and a second group of parahippocampal location-selective neurons. In both item- and location-selective populations, firing rates were significantly higher during successfully encoded trials. These findings are in line with theories of hippocampal indexing, since selective index neurons may act as pointers to neocortical representations. Overall, activation of distinct populations of neurons could directly support the connection of the 'what' and 'where' of episodic memory., (© 2024. The Author(s).)

The attentional blink (AB) refers to an impaired identification of target stimuli (T2), which are presented shortly after a prior target (T1) within a rapid serial visual presentation (RSVP) stream. It has been suggested that the AB is related to a failed transfer of T2 into working memory and that hippocampus (HC) and entorhinal cortex (EC) are regions crucial for this transfer. Since the event-related P3 component has been linked to inhibitory processes, we hypothesized that the hippocampal P3 elicited by T1 may impact on T2 processing within HC and EC. To test this hypothesis, we reanalyzed microwire data from 21 patients, who performed an RSVP task, during intracranial recordings for epilepsy surgery assessment (Reber et al., 2017). We identified T1-related hippocampal P3 components in the local field potentials (LFPs) and determined the temporal onset of T2 processing in HC/EC based on single-unit response onset activity. In accordance with our hypothesis, T1-related single-trial P3 amplitudes at the onset of T2 processing were clearly larger for unseen compared to seen T2-stimuli. Moreover, increased T1-related single-trial P3 peak latencies were found for T2[unseen] versus T2[seen] trials in case of lags 1 to 3, which was in line with our predictions. In conclusion, our findings support inhibition models of the AB and indicate that the hippocampal P3 elicited by T1 plays a central role in the AB., Competing Interests: Declaration of Competing Interest The authors declare that no financial or non-financial competing interests exist., (Copyright © 2023. Published by Elsevier Inc.)

A central function of the human brain is to adapt to new situations based on past experience. Adaptation is reflected behaviorally by shorter reaction times to repeating or similar stimuli, and neurophysiologically by reduced neural activity in bulk-tissue measurements with fMRI or EEG. Several potential single-neuron mechanisms have been hypothesized to cause this reduction of activity at the macroscopic level. We here explore these mechanisms using an adaptation paradigm with visual stimuli bearing abstract semantic similarity. We recorded intracranial EEG (iEEG) simultaneously with spiking activity of single neurons in the medial temporal lobes of 25 neurosurgical patients. Recording from 4917 single neurons, we demonstrate that reduced event-related potentials in the macroscopic iEEG signal are associated with a sharpening of single-neuron tuning curves in the amygdala, but with an overall reduction of single-neuron activity in the hippocampus, entorhinal cortex, and parahippocampal cortex, consistent with fatiguing in these areas., (© 2023. The Author(s).)

Objective: Recently, we showed that resection of at least 27% of the temporal part of piriform cortex (PiC) strongly correlated with seizure freedom 1 year following selective amygdalo-hippocampectomy (tsSAHE) in patients with mesial temporal lobe epilepsy (mTLE). However, the impact of PiC resection on long-term seizure outcome following tsSAHE is currently unknown. The aim of this study was to evaluate the impact of PiC resection on long-term seizure outcome in patients with mTLE treated with tsSAHE., Methods: Between 2012 and 2017, 64 patients were included in the retrospective analysis. Long-term follow-up (FU) was defined as at least 2 years postoperatively. Seizure outcome was assessed according to the International League against Epilepsy (ILAE). The resected proportions of hippocampus, amygdala, and PiC were volumetrically assessed., Results: The mean FU duration was 3.75 ± 1.61 years. Patients with ILAE class 1 revealed a significantly larger median proportion of resected PiC compared to patients with ILAE class 2-6 [46% (IQR 31-57) vs. 16% (IQR 6-38), p = 0.001]. Resected proportions of hippocampus and amygdala did not significantly differ for these groups. Among those patients with at least 27% resected proportion of PiC, there were significantly more patients with seizure freedom compared to the patients with <27% resected proportion of PiC (83% vs. 39%, p = 0.0007)., Conclusions: Our results show a strong impact of the extent of PiC resection on long-term seizure outcome following tsSAHE in mTLE. The authors suggest the PiC to constitute a key target volume in tsSAHE to achieve seizure freedom in the long term., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Mind wandering (MW) and mindfulness have both been reported to be vital moderators of psychological wellbeing. Here, we aim to examine how closely associated these phenomena are and evaluate the psychometrics of measures often used to quantify them. We investigated two samples, one consisting of German-speaking unpaid participants (GUP, n [Formula: see text] 313) and one of English-speaking paid participants (EPP, n [Formula: see text] 228) recruited through MTurk.com. In an online experiment, we collected data using the Mindful Attention Awareness Scale (MAAS) and the sustained attention to response task (SART) during which self-reports of MW and meta-awareness of MW were recorded using experience sampling (ES) probes. Internal consistency of the MAAS was high (Cronbachs [Formula: see text] of 0.96 in EPP and 0.88 in GUP). Split-half reliability for SART measures and self-reported MW was overall good with the exception of SART measures focusing on Nogo trials, and those restricted to SART trials preceding ES in a 10 s time window. We found a moderate negative association between trait mindfulness and MW as measured with ES probes in GUP, but not in EPP. Our results suggest that MW and mindfulness are on opposite sides of a spectrum of how attention is focused on the present moment and the task at hand., (© 2022. The Author(s).)

Arithmetic is a cornerstone of scientifically and technologically advanced human culture, but its neuronal mechanisms are poorly understood. Calculating with numbers requires temporary maintenance and manipulation of numerical information according to arithmetic rules. We explored the brain mechanisms involved in simple arithmetic operations by recording single-neuron activity from the medial temporal lobe of human subjects performing additions and subtractions. We found abstract and notation-independent codes for addition and subtraction in neuronal populations. The neuronal codes of arithmetic in different brain areas differed drastically. Decoders applied to time-resolved recordings demonstrate a static code in hippocampus based on persistently rule-selective neurons, in contrast to a dynamic code in parahippocampal cortex originating from neurons carrying rapidly changing rule information. The implementation of abstract arithmetic codes suggests different cognitive functions for medial temporal lobe regions in arithmetic., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Concept neurons in the medial temporal lobe respond to semantic features of presented stimuli. Analyzing 61 concept neurons recorded from twelve patients who underwent surgery to treat epilepsy, we show that firing patterns of concept neurons encode relations between concepts during a picture comparison task. Thirty-three of these responded to non-preferred stimuli with a delayed but well-defined onset whenever the task required a comparison to a response-eliciting concept, but not otherwise. Supporting recent theories of working memory, concept neurons increased firing whenever attention was directed towards this concept and could be reactivated after complete activity silence. Population cross-correlations of pairs of concept neurons exhibited order-dependent asymmetric peaks specifically when their response-eliciting concepts were to be compared. Our data are consistent with synaptic mechanisms that support reinstatement of concepts and their relations after activity silence, flexibly induced through task-specific sequential activation. This way arbitrary contents of experience could become interconnected in both working and long-term memory., (© 2021. The Author(s).)

Single-unit recordings in the brain of behaving human subjects provide a unique opportunity to advance our understanding of neural mechanisms of cognition. These recordings are exclusively performed in medical centers during diagnostic or therapeutic procedures. The presence of medical instruments along with other aspects of the hospital environment limit the control of electrical noise compared to animal laboratory environments. Here, we highlight the problem of an increased occurrence of simultaneous spike events on different recording channels in human single-unit recordings. Most of these simultaneous events were detected in clusters previously labeled as artifacts and showed similar waveforms. These events may result from common external noise sources or from different micro-electrodes recording activity from the same neuron. To address the problem of duplicate recorded events, we introduce an open-source algorithm to identify these artificial spike events based on their synchronicity and waveform similarity. Applying our method to a comprehensive dataset of human single-unit recordings, we demonstrate that our algorithm can substantially increase the data quality of these recordings. Given our findings, we argue that future studies of single-unit activity recorded under noisy conditions should employ algorithms of this kind to improve data quality.

Auditory beats are amplitude-modulated signals (monaural beats) or signals that subjectively cause the perception of an amplitude modulation (binaural beats). We investigated the effects of monaural and binaural 5 Hz beat stimulation on neural activity and memory performance in neurosurgical patients performing an associative recognition task. Previously, we had reported that these beat stimulation conditions modulated memory performance in opposite directions. Here, we analyzed data from a patient subgroup, in which microwires were implanted in the amygdala, hippocampus, entorhinal cortex and parahippocampal cortex. We identified neurons responding with firing rate changes to binaural versus monaural 5 Hz beat stimulation. In these neurons, we correlated the differences in firing rates for binaural versus monaural beats to the memory-related differences for remembered versus forgotten items and associations. In the left hemisphere, we detected statistically significant negative correlations between firing rate differences for binaural versus monaural beats and remembered versus forgotten items/associations. Importantly, such negative correlations were also observed between beat stimulation-related firing rate differences in the pre-stimulus window and memory-related firing rate differences in the post-stimulus windows. In line with concepts of homeostatic plasticity, our findings suggest that beat stimulation is linked to memory performance via shifting baseline firing levels.

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., Competing Interests: The authors have declared that no competing interests exist.

Deciphering the mechanisms of human memory is a central goal of neuroscience, both from the point of view of the fundamental biology of memory and for its translational relevance. Here, we review some contributions that recordings from neurons in humans implanted with electrodes for clinical purposes have made toward this goal. Recordings from the medial temporal lobe, including the hippocampus, reveal the existence of two classes of cells: those encoding highly selective and invariant representations of abstract concepts, and memory-selective cells whose activity is related to familiarity and episodic retrieval. Insights derived from observing these cells in behaving humans include that semantic representations are activated before episodic representations, that memory content and memory strength are segregated, and that the activity of both types of cells is related to subjective awareness as expected from a substrate for declarative memory. Visually selective cells can remain persistently active for several seconds, thereby revealing a cellular substrate for working memory in humans. An overarching insight is that the neural code of human memory is interpretable at the single-neuron level. Jointly, intracranial recording studies are starting to reveal aspects of the building blocks of human memory at the single-cell level. This work establishes a bridge to cellular-level work in animals on the one hand, and the extensive literature on noninvasive imaging in humans on the other hand. More broadly, this work is a step toward a detailed mechanistic understanding of human memory that is needed to develop therapies for human memory disorders., (Copyright © 2021 the authors.)

The human medial temporal lobe (MTL) has been suggested to play a role in valuation. However, little is known about its role in binary decisions and metacognition. We performed two decision-making tasks while recording from neurons in the human MTL. During a break, subjects consumed their preferred food item to satiation and subsequently repeated both tasks. We identified both a persistent and a transient modulation of the neural activity. Two independent subpopulations of neurons showed a persistent correlation of their firing rates with either decision confidence or reaction times. Importantly, the changes in confidence and reaction time between experimental sets were accompanied by a correlated change in the neural activity, and this correlation lasted as long as it was relevant for the behavioral task. Previous studies have suggested a transient modulation of the neural activity in the human MTL correlated with subjective value. However, in our study, neither subjective value nor unsigned value could explain this transient activity better than the nutritional features of the stimuli, calling into question the role of the human MTL in valuation., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The application of non-linear signal analysis techniques to biomedical data is key to improve our knowledge about complex physiological and pathological processes. In particular, the use of non-linear techniques to study electroencephalographic (EEG) recordings can provide an advanced characterization of brain dynamics. In epilepsy these dynamics are altered at different spatial scales of neuronal organization. We therefore apply non-linear signal analysis to EEG recordings from epilepsy patients derived with intracranial hybrid electrodes, which are composed of classical macro contacts and micro wires. Thereby, these electrodes record EEG at two different spatial scales. Our aim is to test the degree to which the analysis of the EEG recorded at these different scales allows us to characterize the neuronal dynamics affected by epilepsy. For this purpose, we retrospectively analyzed long-term recordings performed during five nights in three patients during which no seizures took place. As a benchmark we used the accuracy with which this analysis allows determining the hemisphere that contains the seizure onset zone, which is the brain area where clinical seizures originate. We applied the surrogate-corrected non-linear predictability score (ψ), a non-linear signal analysis technique which was shown previously to be useful for the lateralization of the seizure onset zone from classical intracranial EEG macro contact recordings. Higher values of ψ were found predominantly for signals recorded from the hemisphere containing the seizure onset zone as compared to signals recorded from the opposite hemisphere. These differences were found not only for the EEG signals recorded with macro contacts, but also for those recorded with micro wires. In conclusion, the information obtained from the analysis of classical macro EEG contacts can be complemented by the one of micro wire EEG recordings. This combined approach may therefore help to further improve the degree to which quantitative EEG analysis can contribute to the diagnostics in epilepsy patients., (Copyright © 2020 Martínez, Niediek, Mormann and Andrzejak.)

Despite its ubiquitous use in medicine, and extensive knowledge of its molecular and cellular effects, how anesthesia induces loss of consciousness (LOC) and affects sensory processing remains poorly understood. Specifically, it is unclear whether anesthesia primarily disrupts thalamocortical relay or intercortical signaling. Here we recorded intracranial electroencephalogram (iEEG), local field potentials (LFPs), and single-unit activity in patients during wakefulness and light anesthesia. Propofol infusion was gradually increased while auditory stimuli were presented and patients responded to a target stimulus until they became unresponsive. We found widespread iEEG responses in association cortices during wakefulness, which were attenuated and restricted to auditory regions upon LOC. Neuronal spiking and LFP responses in primary auditory cortex (PAC) persisted after LOC, while responses in higher-order auditory regions were variable, with neuronal spiking largely attenuated. Gamma power induced by word stimuli increased after LOC while its frequency profile slowed, thus differing from local spiking activity. In summary, anesthesia-induced LOC disrupts auditory processing in association cortices while relatively sparing responses in PAC, opening new avenues for future research into mechanisms of LOC and the design of anesthetic monitoring devices., Competing Interests: The authors declare no competing interest.

[This corrects the article DOI: 10.1371/journal.pbio.3000290.].

Sensory experience elicits complex activity patterns throughout the neocortex. Projections from the neocortex converge onto the medial temporal lobe (MTL), in which distributed neocortical firing patterns are distilled into sparse representations. The precise nature of these neuronal representations is still unknown. Here, we show that population activity patterns in the MTL are governed by high levels of semantic abstraction. We recorded human single-unit activity in the MTL (4,917 units, 25 patients) while subjects viewed 100 images grouped into 10 semantic categories of 10 exemplars each. High levels of semantic abstraction were indicated by representational similarity analyses (RSAs) of patterns elicited by individual stimuli. Moreover, pattern classifiers trained to decode semantic categories generalised successfully to unseen exemplars, and classifiers trained to decode exemplar identity more often confused exemplars of the same versus different categories. Semantic abstraction and generalisation may thus be key to efficiently distill the essence of an experience into sparse representations in the human MTL. Although semantic abstraction is efficient and may facilitate generalisation of knowledge to novel situations, it comes at the cost of a loss of detail and may be central to the generation of false memories., Competing Interests: The authors have declared that no competing interests exist.

Imagine how flicking through your photo album and seeing a picture of a beach sunset brings back fond memories of a tasty cocktail you had that night. Computational models suggest that upon receiving a partial memory cue ('beach'), neurons in the hippocampus coordinate reinstatement of associated memories ('cocktail') in cortical target sites. Here, using human single neuron recordings, we show that hippocampal firing rates are elevated from ~ 500-1500 ms after cue onset during successful associative retrieval. Concurrently, the retrieved target object can be decoded from population spike patterns in adjacent entorhinal cortex (EC), with hippocampal firing preceding EC spikes and predicting the fidelity of EC object reinstatement. Prior to orchestrating reinstatement, a separate population of hippocampal neurons distinguishes different scene cues (buildings vs. landscapes). These results elucidate the hippocampal-entorhinal circuit dynamics for memory recall and reconcile disparate views on the role of the hippocampus in scene processing vs. associative memory.

Our human-specific symbolic number skills that underpin science and technology spring from nonsymbolic set size representations. Despite the significance of numerical competence, its single-neuron mechanisms in the human brain are unknown. We therefore recorded from single neurons in the medial temporal lobe of neurosurgical patients that performed a calculation task. We found that distinct groups of neurons represented either nonsymbolic or symbolic number, but not both number formats simultaneously. Numerical information could be decoded robustly from the population of neurons tuned to nonsymbolic number and with lower accuracy also from the population of neurons selective to number symbols. The tuning characteristics of selective neurons may explain why set size is represented only approximately in behavior, whereas number symbols allow exact assessments of numerical values. Our results suggest number neurons as neuronal basis of human number representations that ultimately give rise to number theory and mathematics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The neuronal mechanisms giving rise to conscious perception remain largely elusive [1]. It is known that the strength of single-neuron activity correlates with conscious perception, especially in anterior regions of the ventral pathway in non-human primates [2-4] and in the human medial temporal lobe (MTL) [5, 6]. It is unclear, however, whether single-neuron correlates of conscious perception are characterized solely by the magnitude of neuronal responses, and whether the correlates of perception are equally prominent across different regions of the human MTL. While recording from 2,735 neurons in 21 neurosurgical patients during 40 experimental sessions, we created experimental conditions in which otherwise identical visual stimuli are sometimes seen and sometimes not detected at all by means of the attentional blink, i.e., the phenomenon that the second of two target stimuli in close succession often goes unnoticed to conscious perception [7]. Remarkably, responses to unseen versus seen stimuli were delayed and temporally more dispersed, in addition to being attenuated in firing rate. This finding suggests precise timing of neuronal responses as a novel candidate physiological marker of conscious perception. In addition, we found modulation of neuronal response timing and strength in response to seen versus unseen stimuli to increase along an anatomical gradient from the posterior to the anterior MTL. Our results thus map out the neuronal correlates of conscious perception in the human MTL both in time and in space., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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 [1-8]. 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Imaging, electrophysiological, and lesion studies have shown a relationship between the parahippocampal cortex (PHC) and the processing of spatial scenes. Our present knowledge of PHC, however, is restricted to the macroscopic properties and dynamics of bulk tissue; the behavior and selectivity of single parahippocampal neurons remains largely unknown. In this study, we analyzed responses from 630 parahippocampal neurons in 24 neurosurgical patients during visual stimulus presentation. We found a spatially clustered subpopulation of scene-selective units with an associated event-related field potential. These units form a population code that is more distributed for scenes than for other stimulus categories, and less sparse than elsewhere in the medial temporal lobe. Our electrophysiological findings provide insight into how individual units give rise to the population response observed with functional imaging in the parahippocampal place area., Competing Interests: The authors declare no conflict of interest.

Recording extracellulary from neurons in the brains of animals in vivo is among the most established experimental techniques in neuroscience, and has recently become feasible in humans. Many interesting scientific questions can be addressed only when extracellular recordings last several hours, and when individual neurons are tracked throughout the entire recording. Such questions regard, for example, neuronal mechanisms of learning and memory consolidation, and the generation of epileptic seizures. Several difficulties have so far limited the use of extracellular multi-hour recordings in neuroscience: Datasets become huge, and data are necessarily noisy in clinical recording environments. No methods for spike sorting of such recordings have been available. Spike sorting refers to the process of identifying the contributions of several neurons to the signal recorded in one electrode. To overcome these difficulties, we developed Combinato: a complete data-analysis framework for spike sorting in noisy recordings lasting twelve hours or more. Our framework includes software for artifact rejection, automatic spike sorting, manual optimization, and efficient visualization of results. Our completely automatic framework excels at two tasks: It outperforms existing methods when tested on simulated and real data, and it enables researchers to analyze multi-hour recordings. We evaluated our methods on both short and multi-hour simulated datasets. To evaluate the performance of our methods in an actual neuroscientific experiment, we used data from from neurosurgical patients, recorded in order to identify visually responsive neurons in the medial temporal lobe. These neurons responded to the semantic content, rather than to visual features, of a given stimulus. To test our methods with multi-hour recordings, we made use of neurons in the human medial temporal lobe that respond selectively to the same stimulus in the evening and next morning., Competing Interests: The authors have declared that no competing interests exist.

Extracellular neuronal microelectrode recordings can include action potentials from multiple neurons. To separate spikes from different neurons, they can be sorted according to their shape, a procedure referred to as spike-sorting. Several algorithms have been reported to solve this task. However, when clustering outcomes are unsatisfactory, most of them are difficult to adjust to achieve the desired results. We present an online spike-sorting framework that uses feature normalization and weighting to maximize the distinctiveness between different spike shapes. Furthermore, multiple criteria are applied to either facilitate or prevent cluster fusion, thereby enabling experimenters to fine-tune the sorting process. We compare our method to established unsupervised offline (Wave&#95;Clus (WC)) and online (OSort (OS)) algorithms by examining their performance in sorting various test datasets using two different scoring systems (AMI and the Adamos metric). Furthermore, we evaluate sorting capabilities on intra-operative recordings using established quality metrics. Compared to WC and OS, our algorithm achieved comparable or higher scores on average and produced more convincing sorting results for intra-operative datasets. Thus, the presented framework is suitable for both online and offline analysis and could substantially improve the quality of microelectrode-based data evaluation for research and clinical application.

Conceptually and structurally simple mathematical models of coupled oscillator networks can show a rich variety of complex dynamics, providing fundamental insights into many real-world phenomena. A recent and not yet fully understood example is the collapse of coexisting synchronous and asynchronous oscillations into a globally synchronous motion found in networks of identical oscillators. Here we show that this sudden collapse is promoted by a further decrease of synchronization, rather than by critically high synchronization. This strikingly counterintuitive mechanism can be found also in nature, as we demonstrate on epileptic seizures in humans. Analyzing spatiotemporal correlation profiles derived from intracranial electroencephalographic recordings (EEG) of seizures in epilepsy patients, we found a pronounced decrease of correlation at the seizure onsets. Applying our findings in a closed-loop control scheme to models of coupled oscillators in chimera states, we succeed in both provoking and preventing outbreaks of global synchronization. Our findings not only advance the understanding of networks of coupled dynamics but can open new ways to control them, thus offering a vast range of potential new applications.

The medial septum/diagonal band of Broca complex (MSDB) is a key structure that modulates hippocampal rhythmogenesis. Cholinergic neurons of the MSDB play a central role in generating and pacing theta-band oscillations in the hippocampal formation during exploration, novelty detection, and memory encoding. How precisely cholinergic neurons affect hippocampal network dynamics in vivo, however, has remained elusive. In this study, we show that stimulation of cholinergic MSDB neurons in urethane-anesthetized mice acts on hippocampal networks via two distinct pathways. A direct septo-hippocampal cholinergic projection causes increased firing of hippocampal inhibitory interneurons with concomitantly decreased firing of principal cells. In addition, cholinergic neurons recruit noncholinergic neurons within the MSDB. This indirect pathway is required for hippocampal theta synchronization. Activation of both pathways causes a reduction in pyramidal neuron firing and a more precise coupling to the theta oscillatory phase. These two anatomically and functionally distinct pathways are likely relevant for cholinergic control of encoding versus retrieval modes in the hippocampus., (Copyright © 2015 the authors 0270-6474/15/358394-17$15.00/0.)

We used a face adaptation paradigm to bias the perception of ambiguous images of faces and study how single neurons in the human medial temporal lobe (MTL) respond to the same images eliciting different percepts. The ambiguous images were morphs between the faces of two familiar individuals, chosen because at least one MTL neuron responded selectively to one but not to the other face. We found that the firing of MTL neurons closely followed the subjects' perceptual decisions--i.e., recognizing one person or the other. In most cases, the response to the ambiguous images was similar to the one obtained when showing the pictures without morphing. Altogether, these results show that many neurons in the medial temporal lobe signal the subjects' perceptual decisions rather than the visual features of the stimulus., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)