Two kinds of memory signals in neurons of the human hippocampus.

Prior studies of the neural representation of episodic memory in the human hippocampus have identified generic memory signals representing the categorical status of test items (novel vs. repeated), whereas other studies have identified item specific memory signals representing individual test items. Here, we report that both kinds of memory signals can be detected in hippocampal neurons in the same experiment. We recorded single-unit activity from four brain regions (hippocampus, amygdala, anterior cingulate, and prefrontal cortex) of epilepsy patients as they completed a continuous recognition task. The generic signal was found in all four brain regions, whereas the item-specific memory signal was detected only in the hippocampus and reflected sparse coding. That is, for the item-specific signal, each hippocampal neuron responded strongly to a small fraction of repeated words, and each repeated word elicited strong responding in a small fraction of neurons. The neural code was sparse, pattern-separated, and limited to the hippocampus, consistent with longstanding computational models. We suggest that the item-specific episodic memory signal in the hippocampus is fundamental, whereas the more widespread generic memory signal is derivative and is likely used by different areas of the brain to perform memory-related functions that do not require item-specific information.

Spiking activity in the human hippocampus prior to encoding predicts subsequent memory.

Encoding activity in the medial temporal lobe, presumably evoked by the presentation of stimuli (postonset activity), is known to predict subsequent memory. However, several independent lines of research suggest that preonset activity also affects subsequent memory. We investigated the role of preonset and postonset single-unit and multiunit activity recorded from epilepsy patients as they completed a continuous recognition task. In this task, words were presented in a continuous series and eventually began to repeat. For each word, the patient's task was to decide whether it was novel or repeated. We found that preonset spiking activity in the hippocampus (when the word was novel) predicted subsequent memory (when the word was later repeated). Postonset activity during encoding also predicted subsequent memory, but was simply a continuation of preonset activity. The predictive effect of preonset spiking activity was much stronger in the hippocampus than in three other brain regions (amygdala, anterior cingulate, and prefrontal cortex). In addition, preonset and postonset activity around the encoding of novel words did not predict memory performance for novel words (i.e., correctly classifying the word as novel), and preonset and postonset activity around the time of retrieval did not predict memory performance for repeated words (i.e., correctly classifying the word as repeated). Thus, the only predictive effect was between preonset activity (along with its postonset continuation) at the time of encoding and subsequent memory. Taken together, these findings indicate that preonset hippocampal activity does not reflect general arousal/attention but instead reflects what we term "attention to encoding."

Hyperactive MEK1 Signaling in Cortical GABAergic Neurons Promotes Embryonic Parvalbumin Neuron Loss and Defects in Behavioral Inhibition.

Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes.

Coding of episodic memory in the human hippocampus.

Neurocomputational models have long posited that episodic memories in the human hippocampus are represented by sparse, stimulus-specific neural codes. A concomitant proposal is that when sparse-distributed neural assemblies become active, they suppress the activity of competing neurons (neural sharpening). We investigated episodic memory coding in the hippocampus and amygdala by measuring single-neuron responses from 20 epilepsy patients (12 female) undergoing intracranial monitoring while they completed a continuous recognition memory task. In the left hippocampus, the distribution of single-neuron activity indicated that only a small fraction of neurons exhibited strong responding to a given repeated word and that each repeated word elicited strong responding in a different small fraction of neurons. This finding reflects sparse distributed coding. The remaining large fraction of neurons exhibited a concurrent reduction in firing rates relative to novel words. The observed pattern accords with longstanding predictions that have previously received scant support from single-cell recordings from human hippocampus.

Sparse and distributed coding of episodic memory in neurons of the human hippocampus.

Neurocomputational models hold that sparse distributed coding is the most efficient way for hippocampal neurons to encode episodic memories rapidly. We investigated the representation of episodic memory in hippocampal neurons of nine epilepsy patients undergoing intracranial monitoring as they discriminated between recently studied words (targets) and new words (foils) on a recognition test. On average, single units and multiunits exhibited higher spike counts in response to targets relative to foils, and the size of this effect correlated with behavioral performance. Further analyses of the spike-count distributions revealed that (i) a small percentage of recorded neurons responded to any one target and (ii) a small percentage of targets elicited a strong response in any one neuron. These findings are consistent with the idea that in the human hippocampus episodic memory is supported by a sparse distributed neural code.

Distributed representation of visual objects by single neurons in the human brain.

It remains unclear how single neurons in the human brain represent whole-object visual stimuli. While recordings in both human and nonhuman primates have shown distributed representations of objects (many neurons encoding multiple objects), recordings of single neurons in the human medial temporal lobe, taken as subjects' discriminated objects during multiple presentations, have shown gnostic representations (single neurons encoding one object). Because some studies suggest that repeated viewing may enhance neural selectivity for objects, we had human subjects discriminate objects in a single, more naturalistic viewing session. We found that, across 432 well isolated neurons recorded in the hippocampus and amygdala, the average fraction of objects encoded was 26%. We also found that more neurons encoded several objects versus only one object in the hippocampus (28 vs 18%, p < 0.001) and in the amygdala (30 vs 19%, p < 0.001). Thus, during realistic viewing experiences, typical neurons in the human medial temporal lobe code for a considerable range of objects, across multiple semantic categories.

Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance--The U.S. E-37 Trial.

OBJECTIVES: The Automatic Stimulation Mode (AutoStim) feature of the Model 106 Vagus Nerve Stimulation (VNS) Therapy System stimulates the left vagus nerve on detecting tachycardia. This study evaluates performance, safety of the AutoStim feature during a 3-5-day Epilepsy Monitoring Unit (EMU) stay and long- term clinical outcomes of the device stimulating in all modes. MATERIALS AND METHODS: The E-37 protocol (NCT01846741) was a prospective, unblinded, U.S. multisite study of the AspireSR(®) in subjects with drug-resistant partial onset seizures and history of ictal tachycardia. VNS Normal and Magnet Modes stimulation were present at all times except during the EMU stay. Outpatient visits at 3, 6, and 12 months tracked seizure frequency, severity, quality of life, and adverse events. RESULTS: Twenty implanted subjects (ages 21-69) experienced 89 seizures in the EMU. 28/38 (73.7%) of complex partial and secondarily generalized seizures exhibited ≥20% increase in heart rate change. 31/89 (34.8%) of seizures were treated by Automatic Stimulation on detection; 19/31 (61.3%) seizures ended during the stimulation with a median time from stimulation onset to seizure end of 35 sec. Mean duty cycle at six-months increased from 11% to 16%. At 12 months, quality of life and seizure severity scores improved, and responder rate was 50%. Common adverse events were dysphonia (n = 7), convulsion (n = 6), and oropharyngeal pain (n = 3). CONCLUSIONS: The Model 106 performed as intended in the study population, was well tolerated and associated with clinical improvement from baseline. The study design did not allow determination of which factors were responsible for improvements.

The established status epilepticus trial 2013.

Benzodiazepine-refractory status epilepticus (established status epilepticus, ESE) is a relatively common emergency condition with several widely used treatments. There are no controlled, randomized, blinded clinical trials to compare the efficacy and tolerability of currently available treatments for ESE. The ESE treatment trial is designed to determine the most effective and/or the least effective treatment of ESE among patients older than 2 years by comparing three arms: fosphenytoin (fPHT) levetiracetam (LVT), and valproic acid (VPA). This is a multicenter, randomized, double-blind, Bayesian adaptive, phase III comparative effectiveness trial. Up to 795 patients will be randomized initially 1:1:1, and response-adaptive randomization will occur after 300 patients have been recruited. Randomization will be stratified by three age groups, 2-18, 19-65, and 66 and older. The primary outcome measure is cessation of clinical seizure activity and improving mental status, without serious adverse effects or further intervention at 60 min after administration of study drug. Each subject will be followed until discharge or 30 days from enrollment. This trial will include interim analyses for early success and futility. This trial will be considered a success if the probability that a treatment is the most effective is >0.975 or the probability that a treatment is the least effective is >0.975 for any treatment. Proposed total sample size is 795, which provides 90% power to identify the most effective and/or the least effective treatment when one treatment arm has a true response rate of 65% and the true response rate is 50% in the other two arms.

Treatment of status epilepticus: an international survey of experts.

BACKGROUND: As part of the development of the Neurocritical Care Society (NCS) Status Epilepticus (SE) Guidelines, the NCS SE Writing Committee conducted an international survey of SE experts. METHODS: The survey consisted of three patient vignettes (case 1, an adult; case 2, an adolescent; case 3, a child) and questions regarding treatment. The questions for each case focused on initial and sequential therapy as well as when to use continuous intravenous (cIV) therapy and for what duration. Responses were obtained from 60/120 (50%) of those surveyed. RESULTS: This survey reveals that there is expert consensus for using intravenous lorazepam for the emergent (first-line) therapy of SE in children and adults. For urgent (second-line) therapy, the most common agents chosen were phenytoin/fosphenytoin, valproate sodium, and levetiracetam; these choices varied by the patient age in the case scenarios. Physicians who care for adult patients chose cIV therapy for RSE, especially midazolam and propofol, rather than a standard AED sooner than those who care for children; and in children, there is a reluctance to choose propofol. Pentobarbital was chosen later in the therapy for all ages. CONCLUSION: There is close agreement between the recently published NCS guideline for SE and this survey of experts in the treatment of SE.

Guidelines for the evaluation and management of status epilepticus.

Status epilepticus (SE) treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. To provide guidance for the acute treatment of SE in critically ill patients, the Neurocritical Care Society organized a writing committee to evaluate the literature and develop an evidence-based and expert consensus practice guideline. Literature searches were conducted using PubMed and studies meeting the criteria established by the writing committee were evaluated. Recommendations were developed based on the literature using standardized assessment methods from the American Heart Association and Grading of Recommendations Assessment, Development, and Evaluation systems, as well as expert opinion when sufficient data were lacking.

Neurons in the human hippocampus and amygdala respond to both low- and high-level image properties.

A large number of studies have demonstrated that structures within the medial temporal lobe, such as the hippocampus, are intimately involved in declarative memory for objects and people. Although these items are abstractions of the visual scene, specific visual details can change the speed and accuracy of their recall. By recording from 415 neurons in the hippocampus and amygdala of human epilepsy patients as they viewed images drawn from 10 image categories, we showed that the firing rates of 8% of these neurons encode image illuminance and contrast, low-level properties not directly pertinent to task performance, whereas in 7% of the neurons, firing rates encode the category of the item depicted in the image, a high-level property pertinent to the task. This simultaneous representation of high- and low-level image properties within the same brain areas may serve to bind separate aspects of visual objects into a coherent percept and allow episodic details of objects to influence mnemonic performance.

Nonlinear dynamics of seizure prediction in a rodent model of epilepsy.

Epilepsy is a dynamical disorder with intermittent crises (seizures) that until recently were considered unpredictable. In this study, we investigated the predictability of epileptic seizures in chronically epileptic rats as a first step towards a subsequent timely intervention for seizure control. We look at the epileptic brain as a nonlinear complex system that undergoes spatio-temporal state transitions and the Lyapunov exponents as indices of its stability. We estimated the spatial synchronization or desynchronization of the maximum short-term Lyapunov exponents (STLmax, approximate measures of chaos) among multiple brain sites over days of electroencephalographic (EEG) recordings from 5 rats that had developed chronic epilepsy according to the lithium pilocarpine rodent model of epilepsy. We utilized this synchronization of EEG dynamics for the construction of a robust seizure prediction algorithm. The parameters of the algorithm were optimized using receiver operator curves (ROCs) on training EEG datasets from each rat for the algorithm to provide maximum sensitivity and specificity in the prediction of their seizures. The performance of the algorithm was then tested on long-term testing EEG datasets per rat. The thus optimized prediction algorithm on the testing datasets over all rats yielded a seizure prediction mean sensitivity of 85.9%, specificity of 0.180 false predictions per hour, and prediction time of 67.6 minutes prior to a seizure onset. This study provides evidence that prediction of seizures is feasible through analysis of the EEG within the framework of nonlinear dynamics, and thus paves the way for just-in-time pharmacological or physiological inter-ventions to abort seizures tens of minutes before their occurrence.

APOE 4 polymorphism results in early cognitive deficits in an EAE model.

Recent clinical studies have identified an association between APOE 4 and cognitive deficits in patients with multiple sclerosis. We induced experimental autoimmune encephalomyelitis (EAE) in APOE knockout (KO) and human APOE 4 knockin (E4) mice to study the interaction of APOE and neuroinflammation on cognition. After EAE induction, KO and E4 showed significant deficits in spatial learning and recall. Regional decreases in choline acetyltransferase localized to the hippocampus. Induction of EAE in a transgenic APOE animal provides a template from which we can decipher the role APOE has on cognition in the context of neuroinflammation.

EEG stages predict treatment response in experimental status epilepticus.

Progression of severity in experimental status epilepticus (SE), defined as refractoriness to first- and second-line abortive agents, may be related to a five-stage progression of electroencephalography (EEG) patterns. This was tested in the lithium-pilocarpine rat SE model. Abortive treatment with diazepam and phenobarbital was given at EEG stages I, III, and V. In stage I, the combination therapy resulted in 100% SE termination. However, stage III corresponded to high treatment resistance (0% abortion) and stage V to an intermediate response (63%). Comparisons of time-to-treatment durations showed overlap between stage I and stage III, despite having markedly different response rates to abortive medications. Therefore, EEG patterns reflect the dynamic pathophysiology of SE and can be used as reliable and specific markers to distinguish treatment-responsive from treatment-refractory SE more accurately than time alone.

Control of synchronization of brain dynamics leads to control of epileptic seizures in rodents.

We have designed and implemented an automated, just-in-time stimulation, seizure control method using a seizure prediction method from nonlinear dynamics coupled with deep brain stimulation in the centromedial thalamic nuclei in epileptic rats. A comparison to periodic stimulation, with identical stimulation parameters, was also performed. The two schemes were compared in terms of their efficacy in control of seizures, as well as their effect on synchronization of brain dynamics. The automated just-in-time (JIT) stimulation showed reduction of seizure frequency and duration in 5 of the 6 rats, with significant reduction of seizure frequency (>50%) in 33% of the rats. This constituted a significant improvement over the efficacy of the periodic control scheme in the same animals. Actually, periodic stimulation showed an increase of seizure frequency in 50% of the rats, reduction of seizure frequency in 3 rats and significant reduction in 1 rat. Importantly, successful seizure control was highly correlated with desynchronization of brain dynamics. This study provides initial evidence for the use of closed-loop feedback control systems in epileptic seizures combining methods from seizure prediction and deep brain stimulation.

The role of the newer antiepileptic drugs in the treatment of generalized convulsive status epilepticus.

The emergency treatment of seizures is an important practical issue, especially the treatment of generalized convulsive status epilepticus (GCSE). Benzodiazepines or older standard antiepileptic drugs (phenobarbital, phenytoin) have typically been used as initial intravenous treatment of GCSE. As new parenteral antiepileptic drugs are developed, and more are on the horizon, questions are raised regarding their role in the treatment of status epilepticus (SE). This review discusses the evidence for the treatment of GCSE, including the newer agents (valproate, levetiracetam). We correlate the treatment of SE with our modern understanding of the underlying neurophysiology and seizure duration.

Single neuron recordings of bilinguals performing in a continuous recognition memory task.

We report the results of a bilingual continuous recognition memory task during which single- and multi-neuron activity was recorded in human subjects with intracranial microwire implants. Subjects (n = 5) were right-handed Spanish-English bilinguals who were undergoing evaluation prior to surgery for severe epilepsy. Subjects were presented with Spanish and English words and the task was to determine whether any given word had been seen earlier in the testing session, irrespective of the language in which it had appeared. Recordings in the left and right hippocampus revealed notable laterality, whereby both Spanish and English items that had been seen previously in the other language (switch trials) triggered increased neural firing in the left hippocampus. Items that had been seen previously in the same language (repeat trials) triggered increased neural firings in the right hippocampus. These results are consistent with theories that propose roles of both the left- and right-hemisphere in real-time linguistic processing. Importantly, this experiment presents the first instance of intracranial recordings in bilinguals performing a task with switching demands.

The Concept of Effective Inflow: Application to Interictal Localization of the Epileptogenic Focus From iEEG.

GOAL: Accurate determination of the epileptogenic focus is of paramount diagnostic and therapeutic importance in epilepsy. The current gold standard for focus localization is from ictal (seizure) onset and thus requires the occurrence and recording of multiple typical seizures of a patient. Localization of the focus from seizure-free (interictal) periods remains a challenging problem, especially in the absence of interictal epileptiform activity. METHODS: By exploring the concept of effective inflow, we developed a focus localization algorithm (FLA) based on directed connectivity between brain sites. Subsequently, using the measure of generalized partial directed coherence over a broad frequency band in FLA for the analysis of interictal periods from long-term (days) intracranial electroencephalographic signals, we identified the brain region that is the most frequent receiver of maximal effective inflow from other brain regions. RESULTS: In six out of nine patients with temporal lobe epilepsy, the thus identified brain region was a statistically significant outlier (p < 0.01) and coincided with the clinically assessed epileptogenic focus. In the remaining three patients, the clinically assessed focus still exhibited the highest inflow, but it was not deemed an outlier (p > 0.01). CONCLUSIONS: These findings suggest that the epileptogenic focus is a region of intense influence from other regions interictally, possibly as a mechanism to keep it under control in seizure-free periods. SIGNIFICANCE: The developed framework is expected to assist with the accurate epileptogenic focus localization, reduce hospital stay and healthcare cost, and provide guidance to treatment of epilepsy via resective surgery or neuromodulation.

Abnormal Capillary Vasodynamics Contribute to Ictal Neurodegeneration in Epilepsy.

Seizure-driven brain damage in epilepsy accumulates over time, especially in the hippocampus, which can lead to sclerosis, cognitive decline, and death. Excitotoxicity is the prevalent model to explain ictal neurodegeneration. Current labeling technologies cannot distinguish between excitotoxicity and hypoxia, however, because they share common molecular mechanisms. This leaves open the possibility that undetected ischemic hypoxia, due to ictal blood flow restriction, could contribute to neurodegeneration previously ascribed to excitotoxicity. We tested this possibility with Confocal Laser Endomicroscopy (CLE) and novel stereological analyses in several models of epileptic mice. We found a higher number and magnitude of NG2+ mural-cell mediated capillary constrictions in the hippocampus of epileptic mice than in that of normal mice, in addition to spatial coupling between capillary constrictions and oxidative stressed neurons and neurodegeneration. These results reveal a role for hypoxia driven by capillary blood flow restriction in ictal neurodegeneration.