Objective: We investigated whether interictal epileptiform discharges (IED) in the human hippocampus are related to impairment of specific memory processes, and which characteristics of hippocampal IED are most associated with memory dysfunction.Methods: Ten patients had depth electrodes implanted into their hippocampi for preoperative seizure localization. EEG was recorded during 2,070 total trials of a short-term memory task, with memory processing categorized into encoding, maintenance, and retrieval. The influence of hippocampal IED on these processes was analyzed and adjusted to account for individual differences between patients.Results: Hippocampal IED occurring in the memory retrieval period decreased the likelihood of a correct response when they were contralateral to the seizure focus (p , 0.05) or bilateral (p , 0.001). Bilateral IED during the memory maintenance period had a similar effect (p , 0.01), particularly with spike-wave complexes of longer duration (p , 0.01). IED during encoding had no effect, and reaction time was also unaffected by IED.Conclusions: Hippocampal IED in humans may disrupt memory maintenance and retrieval, but not encoding. The particular effects of bilateral IED and those contralateral to the seizure focus may relate to neural compensation in the more functional hemisphere. This study provides biological validity to animal models in the study of IED-related transient cognitive impairment. Moreover, it strengthens the argument that IED may contribute to cognitive impairment in epilepsy depending upon when and where they occur. Neurology â 2013;81:18-24 GLOSSARY CI 5 confidence interval; DMTS 5 delayed-match-to-sample task; GEE 5 generalized estimating equations; IAT 5 intracarotid amobarbital testing; IED 5 interictal epileptiform discharges; OR 5 odds ratio; TLE 5 temporal lobe epilepsy.Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults, and is associated with memory impairment, 1,2 which affects psychosocial functioning and quality of life. 3 These deficits are attributed to etiologic changes in the hippocampus such as cell death and synaptic reorganization. 4 However, dynamic factors such as interictal abnormalities evident on EEG may impart an independent contribution to neuropsychological outcome. 5Interictal epileptiform discharges (IED) in the cortex, detected with routine scalp EEG recordings, are associated with transient cognitive impairment.6-12 By extension, it is likely that IED in the mesial temporal lobes may affect cognition given the role of these structures in learning and memory. One study 13 showed a 6% decline in working memory performance related to mesial temporal IED. However, as demonstrated in previous studies of cortical IED, 9,10 the degree of cognitive impact could have been underestimated since the authors did not consider 1) the precise timing of the IED within the memory task trials and 2) the specific components involved in memory processing.Using a rodent model of TLE, 14 we recently found that hippocampal IED w...

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Place cells are hippocampal neurons whose discharge is strongly related to a rat's location in its environment. The existence of place cells has led to the proposal that they are part of an integrated neural system dedicated to spatial navigation, an idea supported by the discovery of strong relationships between place cell activity and spatial problem solving. To further understand such relationships, we examined the discharge of place cells recorded while rats solved a place navigation task. We report that, in addition to having widely distributed firing fields, place cells also discharge selectively while the hungry rat waits in an unmarked goal location to release a food pellet. Such firing is not duplicated in other locations outside the main firing field even when the rat's behavior is constrained to be extremely similar to the behavior at the goal. We therefore propose that place cells provide both a geometric representation of the current environment and a reflection of the rat's expectancy that it is located correctly at the goal. This on-line feedback about a critical aspect of navigational performance is proposed to be signaled by the synchronous activity of the large fraction of place cells active at the goal. In combination with other (prefrontal) cells that provide coarse encoding of goal location, hippocampal place cells may therefore participate in a neural network allowing the rat to plan accurate trajectories in space.

Finding one's way in space requires a distributed neural network to support accurate spatial navigation. In the rat, this network likely includes the hippocampus and its place cells. Although such cells allow the organism to locate itself in the environment, an additional mechanism is required to specify the animal's goal. Here, we show that firing activity of neurons in medial prefrontal cortex (mPFC) reflects the motivational salience of places. We recorded mPFC neurons from rats performing a place navigation task, and found that a substantial proportion of cells in the prelimbic͞infralimbic area had place fields. A much smaller proportion of cells with such properties was found in the dorsal anterior cingulate area. Furthermore, the distribution of place fields in prelimbic͞infralimbic cells was not homogeneous: goal locations were overrepresented. Because such locations were spatially dissociated from rewards, we suggest that mPFC neurons might be responsible for encoding the rat's goals, a process necessary for path planning.goal coding ͉ place navigation ͉ unit recording

Hippocampus place cell discharge is an important model system for understanding cognition, but evidence is missing that the place code is under the kind of dynamic attentional control characterized in primates as selective activation of one neural representation and suppression of another, competing representation. We investigated the apparent noise ("overdispersion") in the CA1 place code, hypothesizing that overdispersion results from discharge fluctuations as spatial attention alternates between distal cues and local/self-motion cues. The hypothesis predicts that: (1) preferential use of distal cues will decrease overdispersion; (2) global, attention-like states can be decoded from ensemble discharge such that both the discharge rates and the spatial firing patterns of individual cells will be distinct in the two states; (3) identifying attention-like states improves reconstructions of the rat's path from ensemble discharge. These predictions were confirmed, implying that a covert, dynamic attention-like process modulates discharge on a ϳ1 s time scale. We conclude the hippocampus place code is a dynamic representation of the spatial information in the immediate focus of attention.

Objective-Cognitive impairment is common in epilepsy, particularly in memory function. Interictal spikes are thought to disrupt cognition, but it is difficult to delineate their contribution from general impairments in memory produced by etiology and seizures. We investigated the transient impact of focal interictal spikes on the hippocampus, a structure crucial for learning and memory and yet highly prone to interictal spikes in temporal lobe epilepsy.Methods-Bilateral hippocampal depth electrodes were implanted into fourteen Sprague-Dawley rats, followed by intrahippocampal pilocarpine or saline infusion unilaterally. Rats that developed chronic spikes were trained in a hippocampal-dependent operant behavior task, delayed-match-tosample. Depth EEG was recorded during 5,562 trials among five rats, and within-subject analyses evaluated the impact of hippocampal spikes on short-term memory operations.Results-Hippocampal spikes that occurred during memory retrieval strongly impaired performance (p<0.001). However, spikes that occurred during memory encoding or memory maintenance did not affect performance in those trials. Hippocampal spikes also affected response latency, adding approximately 0.48 seconds to the time taken to respond (p<0.001).Interpretation-We found that focal interictal spike-related interference in cognition extends to structures in the limbic system, which required intrahippocampal recordings. Hippocampal spikes seem most harmful if they occur when hippocampal function is critical, extending human studies showing that cortical spikes are most disruptive during active cortical functioning. The cumulative effects of spikes could therefore impact general cognitive functioning. These results strengthen the argument that suppression of interictal spikes may improve memory and cognitive performance in patients with epilepsy.

In the hippocampus, pyramidal cells encode information in two major ways: rate coding and temporal coding. Rate coding, in which information is coded through firing frequency, is exemplarily illustrated by place cells, characterized by their location-specific firing. In addition, the precise temporal organization of firing of multiple place cells provides information, in a compressed time window, about the temporal sequence of the locations visited by the animal. This encoding is accomplished through phase precession, a phenomenon whereby unit firing is linked to theta rhythm, one of the major hippocampal EEG oscillations. Although it is likely that this type of processing is critical for normal brain function, its involvement in pathologies associated with cognitive disorders is unknown. In this experiment, we determined whether the temporal organization of place cell firing is affected in an animal model of mesial temporal lobe epilepsy (MTLE), a disease accompanied with cognitive impairment. We investigated hippocampal coding and its relationship to theta rhythm in rats after status epilepticus (SE), a condition that leads to MTLE. We found a great proportion of SE place cells had aberrant phase/precession pattern and temporal organization of firing among pairs of neurons, which constitutes the compression of temporal sequences, was altered in SE rats. The same animals were also markedly impaired in the water maze task, a measure of spatial memory. We propose that the synaptic and cellular alterations observed in MTLE induce aberrant temporal coding in the hippocampus, contributing in turn to cognitive dysfunction.

Humans can recognize and navigate in a room when its contents have been rearranged. Rats also adapt rapidly to movements of objects in a familiar environment. We therefore set out to investigate the neural machinery that underlies this capacity by further investigating the place cell–based map of the surroundings found in the rat hippocampus. We recorded from single CA1 pyramidal cells as rats foraged for food in a cylindrical arena (the room) containing a tall barrier (the furniture). Our main finding is a new class of cells that signal proximity to the barrier. If the barrier is fixed in position, these cells appear to be ordinary place cells. When, however, the barrier is moved, their activity moves equally and thereby conveys information about the barrier's position relative to the arena. When the barrier is removed, such cells stop firing, further suggesting they represent the barrier. Finally, if the barrier is put into a different arena where place cell activity is changed beyond recognition (“remapping”), these cells continue to discharge at the barrier. We also saw, in addition to barrier cells and place cells, a small number of cells whose activity seemed to require the barrier to be in a specific place in the environment. We conclude that barrier cells represent the location of the barrier in an environment-specific, place cell framework. The combined place + barrier cell activity thus mimics the current arrangement of the environment in an unexpectedly realistic fashion.