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Objective: To ascertain factors that are related to the antiepileptic drug load in epilepsy. Methods: In this cross‐sectional study, we analyzed a large cohort of conservatively treated patients with epilepsy (n = 1135) and a smaller homogeneous group of presurgical patients with neuropathologically confirmed unilateral hippocampal sclerosis (n = 91). Considered clinical variables comprised (1) presence of an underlying cerebral lesion, (2) onset and (3) duration of epilepsy, (4) seizure frequency, (5) generalized or focal to bilateral tonic‐clonic seizures, (6) ictal impairment of awareness, and (7) a history of convulsive status epilepticus. In the presurgical sample, we additionally considered (8) the degree of pathology (hippocampal neuronal cell densities) instead of (1) presence of a cerebral lesion and (9) an overall rating of epilepsy severity (GASE scale). Drug load was quantified as (a) the number of concomitant antiepileptic drugs (AEDs) and (b) the total defined daily dose (DDD). Results: Analyses disclosed only small correlations between clinical variables and drug load indices. In the conservatively treated cohort, the multiple regression analyses revealed that epilepsy onset, cerebral lesion, history of convulsive status epilepticus, and seizure frequency combined explained only 6%–10% of variance in drug load. Nearly the same variance (5%–8%) could be explained by duration of epilepsy alone. Degree of hippocampal pathology and the epilepsy severity ratings were not related to drug load indices. Significance: Clinical markers of epilepsy severity were only marginally associated with drug load. Findings rather indicate that patients seem to accumulate drugs due to the chronicity of epilepsy. Overall, the drug load remained largely unexplained. The findings nevertheless call for scrutinizing multidrug therapies in patients with long‐lasting epilepsies. [ABSTRACT FROM AUTHOR]

Objective: Assess occurrence of the dendritic spine scaffolding protein Drebrin as a pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms.Methods: Sera of 4 patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches, ranging from immunoblotting, immunoprecipitation, mass spectrometry, subcellular binding pattern analyses in primary neuronal cultures, and immunohistochemistry in brains of wild-type and Drebrin knockout mice to in vitro analyses of impaired synapse formation, morphology, and aberrant neuronal excitability by antibody exposure.Results: In the serum of a patient with adult onset epilepsy and suspected encephalitis, a strong signal at ∼70kDa was detected by immunoblotting, for which mass spectrometry revealed Drebrin as the putative antigen. Three other patients whose sera also showed strong immunoreactivity around 70kDa on Western blotting were also anti-Drebrin-positive. Seizures, memory impairment, and increased protein content in cerebrospinal fluid occurred in anti-Drebrin-seropositive patients. Alterations in cerebral magnetic resonance imaging comprised amygdalohippocampal T2-signal increase and hippocampal sclerosis. Diagnostic biopsy revealed T-lymphocytic encephalitis in an anti-Drebrin-seropositive patient. Exposure of primary hippocampal neurons to anti-Drebrin autoantibodies resulted in aberrant synapse composition and Drebrin distribution as well as increased spike rates and the emergence of burst discharges reflecting network hyperexcitability.Interpretation: Anti-Drebrin autoantibodies define a chronic syndrome of recurrent seizures and neuropsychiatric impairment as well as inflammation of limbic and occasionally cortical structures. Immunosuppressant therapies should be considered in this disorder. ANN NEUROL 2020;87:869-884. [ABSTRACT FROM AUTHOR]

Events that violate predictions are thought to not only modulate activity within the hippocampus and PFC but also enhance communication between the two regions. Scalp and intracranial EEG studies have shown that oscillations in the theta frequency band are enhanced during processing of contextually unexpected information. Some theories suggest that the hippocampus and PFC interact during processing of unexpected events, and it is possible that theta oscillations may mediate these interactions. Here, we had the rare opportunity to conduct simultaneous electrophysiological recordings from the human hippocampus and PFC from two patients undergoing presurgical evaluation for pharmacoresistant epilepsy. Recordings were conducted during a task that involved encoding of contextually expected and unexpected visual stimuli. Across both patients, hippocampal–prefrontal theta phase synchronization was significantly higher during encoding of contextually unexpected study items, relative to contextually expected study items. Furthermore, the hippocampal–prefrontal theta phase synchronization was larger for contextually unexpected items that were later remembered compared with later forgotten items. Moreover, we did not find increased theta synchronization between the PFC and rhinal cortex, suggesting that the observed effects were specific to prefrontal–hippocampal interactions. Our findings are consistent with the idea that theta oscillations orchestrate communication between the hippocampus and PFC in support of enhanced encoding of contextually deviant information. [ABSTRACT FROM AUTHOR]

The theta-gamma neural coding theory suggests that multiple items are represented in working memory (WM) by a superposition of gamma cycles on theta oscillations. To enable a stable, non-interfering representation of multiple items, such a theta-gamma neural code may be reflected by phase-phase coupling, i.e., a precise locking of gamma subcycles to specific theta phases. Recent data have indicated that the hippocampus critically contributes to multi-item working memory. Therefore, we investigated phase-phase coupling patterns in the hippocampus based on intracranial EEG recordings in presurgical epilepsy patients performing a variant of the serial Sternberg WM task. In accordance with predictions of the theta-gamma coding theory, we observed increased phase-phase coupling between theta and beta/gamma activity during working memory maintenance compared to inter-trial intervals. These phase-phase coupling patterns were apparent during maintenance of two and four items, but not during maintenance of a single item, where prominent lower coupling ratios occurred. Furthermore, we observed that load-dependent changes of coupling factors correlated with individual WM capacities. Our data demonstrate that multi-item WM is associated with changes in hippocampal phase-phase coupling between theta and beta/gamma activity. [ABSTRACT FROM PUBLISHER]

During systems-level consolidation, mnemonic representations initially reliant on the hippocampus are thought to migrate to neocortical sites for more permanent storage, with an eminent role of sleep for facilitating this information transfer. Mechanistically, consolidation processes have been hypothesized to rely on systematic interactions between the three cardinal neuronal oscillations characterizing non-rapid eye movement (NREM) sleep. Under global control of de- and hyperpolarizing slow oscillations (SOs), sleep spindles may cluster hippocampal ripples for a precisely timed transfer of local information to the neocortex. We used direct intracranial electroencephalogram recordings from human epilepsy patients during natural sleep to test the assumption that SOs, spindles and ripples are functionally coupled in the hippocampus. Employing cross-frequency phase-amplitude coupling analyses, we found that spindles were modulated by the up-state of SOs. Notably, spindles were found to in turn cluster ripples in their troughs, providing fine-tuned temporal frames for the hypothesized transfer of hippocampal memory traces. [ABSTRACT FROM AUTHOR]

Purpose Magnetic resonance imaging ( MRI) is a key technology in the presurgical evaluation of patients with epilepsy. Already at early outpatient stages it can contribute to the identification of patients who are, in the case of pharmacoresistance, good candidates for epilepsy surgery. Yet, 'standard head' MRI examinations often fail to displaying therapeutically relevant epileptogenic lesions. The purpose of this study is to identify an epilepsy-specific MRI protocol, which is likewise sensitive for even small epileptogenic lesions and economical enough to be applied outside specialized epilepsy centers. Methods Based on a large European presurgical epilepsy program comprising 2,740 patients we identified the spectrum of common epileptogenic lesions and determine the set of MRI sequences that are required for their reliable detection. Relying on a series of small, therapeutically particularly relevant lesions we determined the required slices thickness, slice angulations, and orientations for an epilepsy-specific MRI protocol. Key Findings Indispensable for early outpatient epilepsy specific MRI are fluid attenuated inversion recovery ( FLAIR), T2-weighted, T1-weighted, and hemosiderin/calcification-sensitive sequences. Slice thickness for T2 and FLAIR must not exceed 3 mm. The T1 image should be acquired in three-dimensional technique at 1 mm isotropic voxels size. For T2 and FLAIR, at least two slice orientations each must be demanded in hippocampal angulation. We suggest no adaption to a clinical focus hypothesis. The resulting 'essential 6' sequence protocol allows the detection of virtually all common epileptogenic lesion entities. Significance The creation of a broadly accepted and abundantly applied MRI protocol for epilepsy outpatients can contribute to improved and earlier identification of potential candidates for epilepsy surgery. Our systematic analysis of MRI requirements for the detection of epileptogenic lesions can serve as basis for protocol negotiations between epileptologists, radiologists, and health care funders. [ABSTRACT FROM AUTHOR]

Abstract: Zero-lag phase synchronization of EEG activity has been reported to be a central mechanism accompanying long-term memory formation. In this pilot study, we examined the effects of synchronous low-amplitude stimulation of the rhinal cortex and the hippocampus in eleven temporal lobe epilepsy patients. The impact of in-phase stimulation (zero lag) on long-term memory encoding of words was contrasted with anti-phase (180° phase lag) and sham stimulation. We hypothesized more correctly remembered words for the in-phase compared to the sham condition and fewer correctly remembered words for the anti-phase vs. the sham condition. Indeed, we observed a trend for a linear condition effect for correctly remembered words, which is in accordance to our prediction (in-phase > sham > anti-phase). This finding suggests that even weak synchronous deep brain stimulation of rhinal cortex and hippocampus may modulate memory performance, while clear evidence for an enhancement of memory by this kind of deep brain simulation is still lacking. [Copyright &y& Elsevier]

Objective In temporal lobe epilepsy surgery, there is a trend towards becoming more selective in order to achieve seizure control with an optimal neuropsychological outcome. The present study evaluated whether mesial resection length matters for memory outcome after selective amygdalohippocampectomy (SAH). Therefore, a sub-analysis of the larger SFB/TR3/A1 multicentre randomised trial on seizure outcome and mesial resection length in temporal lobe surgery was performed. Methods A homogeneous group of 67 selectively operated patients with hippocampal sclerosis as the sole pathology were allocated to a short (2.5 cm, n¼34) or a long (3.5 cm, n¼33) mesial resection. Repeated memory assessment and three-dimensional MRI data sets served as dependent within group variables, and intraoperatively determined resection lengths (short/long), resected hippocampal volumes (small/large) and side of surgery were independent between group variables. Results Resection length did not have a significant effect on seizure or on memory outcome. The resected hippocampal volume also did not affect seizure outcome but it did make a difference with regard to memory outcome. Outcome in verbal learning and memory was poorer after resection of larger left hippocampal volumes. Figural memory outcome was poorer with larger resected volumes on either side. Interpretation The data indicate that in SAH, mesial resection length and resected volumes have no differential effect on seizure outcome. The findings on memory outcome are best explained by suggesting that hippocampal volumes take the degree of preoperative pathology into account whereas resection length does not. This suggests resection of non-pathological functional tissues as the basis for memory outcome after SAH. [ABSTRACT FROM AUTHOR]

Not only poststimulus, but also prestimulus neural activity has been shown to be predictive for later successful memory encoding. However, it is still not clear which medial temporal lobe processes precede effective memory formation. Here, our aim was to investigate whether such prestimulus markers for successful memory encoding can be specified based on intracranial recordings directly from the hippocampus and rhinal cortex. For this purpose, we analyzed subsequent memory effects during a continuous word recognition paradigm in 31 presurgical epilepsy patients. We found that rhinal and hippocampal theta and successive alpha power enhancement before word presentation predicted successful memory encoding. Previous studies suggest that stimulus-triggered hippocampal theta activity is particularly related to memory retrieval and activation of a mnemonic context, whereas the alpha rhythm reflects inhibitory top-down control of task processing and executive functioning. In line with these suggestions, we propose that the observed medial temporal theta and alpha power increases before stimulus presentation reflect activation of contextual information and inhibitory top-down control processes preparing for stimulus-triggered memory processing. [ABSTRACT FROM AUTHOR]

Recent findings indicate that the hippocampus supports not only longterm memory encoding but also plays a role in working memory MM) maintenance of multiple items; however, the neural mechanism underlying multi-item maintenance is still unclear. Theoretical work suggests that multiple items are being maintained by neural assemblies synchronized in the gamma frequency range (25-100 Hz) that are locked to consecutive phase ranges of oscillatory activity in the theta frequency range (4-8 Hz). Indeed, cross-frequency coupling of the amplitude of high-frequency activity to the phase of slower oscillations has been described both in animals and in humans, but has never been linked to a theoretical model of a cognitive process. Here we used intracranial EEG recordings in human epilepsy patients to test pivotal predictions from theoretical work. First, we show that simultaneous maintenance of multiple items in WM is accompanied by cross-frequency coupling of oscillatory activity in the hippocampus, which is recruited dunng multiitem WM. Second, maintenance of an increasing number of items is associated with modulation of beta/gamma amplitude with theta band activity of lower frequency, consistent with the idea that longer cycles are required for an increased number of representations by gamma cycles. This effect cannot be explained by a difference in theta or beta! gamma power. Third, we describe how the precision of cross-frequency coupling predicts individual WM performance. These data support the idea that working memory in humans depends on a neural code using phase information. [ABSTRACT FROM AUTHOR]

Two-step theories of memory formation suggest that an initial encoding stage, during which transient neural assemblies are formed in the hippocampus, is followed by a second step called consolidation, which involves re-processing of activity patterns and is associated with an increasing involvement of the neocortex. Several studies in human subjects as well as in animals suggest that memory consolidation occurs predominantly during sleep (standard consolidation model). Alternatively, it has been suggested that consolidation may occur during waking state as well and that the role of sleep is rather to restore encoding capabilities of synaptic connections (synaptic downscaling theory). Here, we review the experimental evidence favoring and challenging these two views and suggest an integrative model of memory consolidation. [ABSTRACT FROM AUTHOR]

The dentate gyrus (DG) plays a pivotal role in the functional and anatomical organization of the hippocampus and is involved in learning and memory formation. However, the impact of structural DG abnormalities, i.e., granule cell dispersion (GCD), for hippocampal seizure susceptibility and its association with distinct lesion patterns in epileptic disorders, such as mesial temporal sclerosis (MTS) remains enigmatic and a large spectrum of pathological changes has been recognized. Here, we propose a clinico-pathological classification of DG pathology based on the examination of 96 surgically resected hippocampal specimens obtained from patients with chronic temporal lobe epilepsy (TLE). We observed three different histological patterns. (1) A normal granule cell layer was identified in 11 patients (no-GCP; 18.7%). (2) Substantial granule cell loss was evident in 36 patients (referred to as granule cell pathology (GCP) Type 1; 37.5%). (3) Architectural abnormalities were observed in 49 specimens, including one or more of the following features: granule cell dispersion, ectopic neurons or clusters of neurons in the molecular layer, or bi-lamination (GCP Type 2; 51%). Cell loss was always encountered in this latter cohort. Seventy-eight patients of our present series suffered from MTS (81.3%). Intriguingly, all MTS patients displayed a compromised DG, 31 (40%) with significant cell loss (Type 1) and 47 (60%) with GCD (Type 2). In 18 patients without MTS (18.7%), seven displayed focally restricted DG abnormalities, either cell loss ( n = 5) or GCD ( n = 2). Clinical histories revealed a significant association between DG pathology patterns and higher age at epilepsy surgery ( p = 0.008), longer epilepsy duration ( p = 0.004), but also with learning dysfunction ( p < 0.05). There was no correlation with the extent of pyramidal cell loss in adjacent hippocampal segments nor with postsurgical seizure relief. The association with long-term seizure histories and cognitive dysfunction is remarkable and may point to a compromised regenerative capacity of the DG in this cohort of TLE patients. [ABSTRACT FROM AUTHOR]

Previous findings indicate that the hippocampus does not only play a role in long-term memory (LTM) encoding, but is important for working memory (WM) as well, in particular when multiple items are being processed. A recent study showed that maintenance of multiple items was associated with hippocampal activation (hippocampus-dependent WM), while maintenance of individual items induced hippocampal deactivations (hippocampus-independent WM). Here, we used two complimentary approaches to investigate whether WM-related activity patterns occur also during LTM encoding of sequentially presented items and whether they are related to the primacy effect, i.e., improved LTM encoding of items presented at the beginning of the list. Intracranial electroencephalogram in epilepsy patients and functional MRI in healthy subjects were recorded during a word-list learning task. As expected, the proportion of successfully encoded items was higher at the beginning of the list than at later list positions. Items at the beginning of the list which were subsequently forgotten were associated with negative blood oxygen level dependent responses and positive direct current slopes, corresponding to hippocampal deactivations, suggesting that they were not processed in hippocampus-dependent WM. These deactivations were absent for items later in the list and for subsequently remembered items. These data show that if processing of items at the beginning of the list is accompanied by hippocampal activity patterns previously observed during hippocampus-dependent WM, these items are subsequently remembered. However, deactivations of the hippocampus as previously observed during WM maintenance of individual items predicts failure of LTM encoding. [ABSTRACT FROM AUTHOR]

Abstract: There is no reasonable doubt that the hippocampus plays an important role in memory processing. A virtually uncountable number of studies in animals and humans have revealed changes in neural activity in this structure during memory formation [Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 1992;99:195–231; Squire LR, Stark CE, Clark RE. The medial temporal lobe. Annu Rev Neurosci 2004;27:279–306], and hippocampal damage reliably leads to impairments in a large number of memory tests. However, while several correlates of successful memory formation have been found in the hippocampus, it is still an open question why specific neural processes support encoding of a particular item. An answer to this question would help to resolve current debates about which memory functions are actually supported by the hippocampus, and why activity in the neural networks of the hippocampus is involved in, or even necessary for, some memory processes but not for others. In this review, we first summarize findings on the electrophysiological activity within the hippocampus during different memory processes. We try to differentiate whether the hippocampus is merely involved in these processes, or whether the hippocampus appears to be necessary for them. Based on a distinction between a more general “encoding state” and the more specific process of “content-specific memory formation”, we review data on neural representations within hippocampus and neocortex. We suggest that during memory formation, the hippocampus renders neural representations more sparse by providing an inhibitory signal to the neocortex. [Copyright &y& Elsevier]

The human hippocampus is essential for both encoding and recollection, but it remains controversial whether there is a functionally different involvement of anterior versus posterior parts of the hippocampus in these memory processes. In the present study, we examined encoding and retrieval processes via intrahippocampal recordings in 27 patients with unilateral temporal lobe epilepsy. Multicontact depth electrodes were implanted along the longitudinal axis of the hippocampus as part of the presurgical evaluation. In a continuous word recognition test, subjects had to indicate whether words were new or already presented. Recognized old words, as compared to new words, resulted in a larger P600 component, as well as in a larger late negative component (LNC, 600-900 msec). In addition, subsequently remembered words elicited a larger positivity (400 to 900 msec) than later forgotten words. We found differences concerning the distribution along the hippocampus for the LNC old-new effect, reflecting successful retrieval, as well as for the subsequent memory effect, reflecting successful encoding. Both effects were larger the further posterior an electrode was located in the hippocampus. Findings are suggestive for a predominant posterior hippocampal involvement in both verbal encoding and retrieval. [ABSTRACT FROM AUTHOR]

Purpose: Selective amygdalohippocampectomy (SAH) is a surgical treatment option for patients with medically intractable mesial temporal lobe epilepsy. In contrast to standard anterior temporal lobectomy, resection of unaffected tissue is limited, although it achieves equal seizure outcomes in selected patients. In SAH, the mesial structures can be approached by different routes, the transsylvian approach and the transcortical approach. Advantages or disadvantages with respect to postoperative cognitive outcome are still a matter of debate. Methods: Eighty randomized patients were included in the analyses. In 41 patients, the transsylvian approach, and in 39 patients, the transcortical approach was performed. All patients received comprehensive neuropsychological testing of verbal and nonverbal memory, attention, and executive functions before and 6 months or 1 year after SAH. Results: Seventy-five percent of patients became completely seizure free with no difference depending on the chosen approach. Repeated measures multivariate analysis of variance (MANOVA) showed that cognitive outcomes after both approaches were essentially the same. The only exception was phonemic fluency, which was significantly improved after transcortical but not after transsylvian SAH. Conclusions: The results indicate that either surgical approach can be chosen independent of cognitive outcome criteria. Improvement in phonemic fluency after transcortical SAH may reflect selective normalization of cognitive function after epilepsy surgery, whereas frontal lobe manipulation might have hindered recovery of this function after transsylvian SAH. [ABSTRACT FROM AUTHOR]

Epileptic activity evokes profound alterations of hippocampal organization and function. Genomic responses may reflect immediate consequences of excitatory stimulation as well as sustained molecular processes related to neuronal plasticity and structural remodeling. Using oligonucleotide microarrays with 8799 sequences, we determined subregional gene expression profiles in rats subjected to pilocarpine-induced epilepsy (U34A arrays, Affymetrix, Santa Clara, CA, USA; P < 0.05, twofold change, n = 3 per stage). Patterns of gene expression corresponded to distinct stages of epilepsy development. The highest number of differentially expressed genes (dentate gyrus, approx. 400 genes and CA1, approx. 700 genes) was observed 3 days after status epilepticus. The majority of up-regulated genes was associated with mechanisms of cellular stress and injury – 14 days after status epilepticus, numerous transcription factors and genes linked to cytoskeletal and synaptic reorganization were differentially expressed and, in the stage of chronic spontaneous seizures, distinct changes were observed in the transcription of genes involved in various neurotransmission pathways and between animals with low vs. high seizure frequency. A number of genes ( n = 18) differentially expressed during the chronic epileptic stage showed corresponding expression patterns in hippocampal subfields of patients with pharmacoresistant temporal lobe epilepsy ( n = 5 temporal lobe epilepsy patients; U133A microarrays, Affymetrix; covering 22 284 human sequences). These data provide novel insights into the molecular mechanisms of epileptogenesis and seizure-associated cellular and structural remodeling of the hippocampus. [ABSTRACT FROM AUTHOR]

For neuroprotective therapy of neurodegenerative diseases creatine treatment has gained special interest because creatine has been shown to cross the blood–brain barrier, accumulate in the human brain in vivo and cause delayed neuronal cell death in a large number of animal models. Here, we used the pilocarpine model of temporal lobe epilepsy to determine whether creatine administration is able to attenuate the epilepsy-associated decrease in hippocampal N -acetyl aspartate (NAA) concentrations, impairment of mitochondrial function and neuronal cell loss. In vivo1 H-NMR spectroscopy showed, in epileptic rats after creatine administration, higher hippocampal NAA concentrations, suggesting improved neuronal survival. However, in vitro observation of hippocampal slices from creatine-treated epileptic rats revealed a more pronounced loss of pyramidal neurons and decrease in activity of mitochondrial enzymes in hippocampal subfields. This indicates that NAA concentrations measured by in vivo1 H-NMR spectroscopy reflect alterations of metabolism rather than neuronal cell densities. Our data indicate an adverse effect of creatine on neuronal survival under conditions of enhanced neuronal activity. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Interictal [18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET) demonstrates temporal hypometabolism in the epileptogenic zone of 60–90% of patients with temporal lobe epilepsy. The pathophysiology of this finding is still unknown. Several studies failed to show a correlation between hippocampal FDG-PET hypometabolism and neuronal cell loss. Because FDG is metabolized by hexokinase bound to the outer mitochondrial membrane, we correlated the glucose-oxidation capacity of hippocampal subfields obtained after surgical resection with the corresponding hippocampal presurgical FDG-PET activity. Methods: In 16 patients with electrophysiologically confirmed temporal lobe epilepsy, we used high-resolution respirometry to determine the basal and maximal glucose-oxidation rates in 400-μm-thick hippocampal subfields obtained after dissection of human hippocampal slices into the CA1 and CA3 pyramidal subfields and the dentate gyrus. Results: We observed a correlation of the FDG-PET activity with the maximal glucose-oxidation rate of the CA3 pyramidal subfields (rp = 0.7, p = 0.003) but not for the regions CA1 and dentate gyrus. In accordance with previous studies, no correlation of the FDG-PET to the neuronal cell density of CA1, CA3, and dentate gyrus was found. Conclusions: The interictal hippocampal FDG-PET hypometabolism in patients with temporal lobe epilepsy is correlated to the glucose-oxidation capacity of the CA3 hippocampal subfield as result of impaired oxidative metabolism. [ABSTRACT FROM AUTHOR]

Abstract Mitochondrial function is a key determinant of both excitability and viability of neurons. Here, we demonstrate seizure-dependent changes in mitochondrial oxidative phosphorylation in the epileptic rat hippocampus. The intense pathological neuronal activity in pilocarpine-treated rats exhibiting spontaneous seizures resulted in a selective decline of the activities of NADH–CoQ oxidoreductase (complex I of the respiratory chain) and cytochrome c oxidase (complex IV of respiratory chain) in the CA3 and CA1 hippocampal pyramidal subfields. In line with these findings, high-resolution respirometry revealed an increased flux control of complex I on respiration in the CA1 and CA3 subfields and decreased maximal respiration rates in the more severely affected CA3 subfield. Imaging of mitochondrial membrane potential using rhodamine 123 showed a lowered mitochondrial membrane potential in both pyramidal subfields. In contrast to the CA1 and CA3 subfields, mitochondrial oxidative phosphorylation was unaltered in the dentate gyrus and the parahippocampal gyrus. The changes of oxidative phosphorylation in the epileptic rat hippocampus cannot be attributed to oxidative enzyme modifications but are very likely related to a decrease in mitochondrial DNA copy number as shown in the more severely affected CA3 subfield and in cultured PC12 cells partially depleted of mitochondrial DNA. Thus, our results demonstrate that seizure activity downregulates the expression of mitochondrial-encoded enzymes of oxidative phosphorylation. This mechanism could be invoked during diverse forms of pathological neuronal activity and could severely affect both excitability and viability of hippocampal pyramidal neurons. [ABSTRACT FROM AUTHOR]

Summary: Purpose: The technique of selective amygdalohippocampectomy (SAH) was originally developed in epilepsy surgery to spare unaffected brain tissue from surgery, thus minimizing the cognitive consequences of temporal lobe surgery. The results of previous studies, however, are equivocal in this regard. This study evaluated memory after SAH in a large sample of patients with mesial temporal lobe epilepsy. Methods: The 140 patients received material-specific memory tests before and 3 months after unilateral SAH. Results: Significant declines in all aspects of verbal learning and memory were found particularly for the left resected group. With reliability-of-change indices, a high number of patients showed postoperative verbal memory declines, ≤51% in left SAH and ≤32% in right SAH. For left SAH, a higher preoperative verbal memory performance, a lower preoperative nonverbal memory score, an older age at surgery, and a later onset of epilepsy predicted a stronger decline in verbal memory. After right SAH, the risk for a verbal memory decline was slightly increased when patients had surgical complications or a presurgical evaluation with bilateral intrahippocampal depth electrodes. Results concerning nonverbal memory were less clear. Conclusions: The results clearly indicate, that particularly left SAH can lead to a significant decline in memory functions. Predictors of postoperative verbal memory were similar to those reported for temporal lobectomy. Postoperative deteriorations were broader and stronger in our study than in previous studies. We discuss methodologic differences (sample size, retest interval, extent of resection) and other factors as possible reasons. [ABSTRACT FROM AUTHOR]

In humans, distinct processes within the hippocampus and rhinal cortex support declarative memory formation. But do these medial temporal lobe (MTL) substructures directly cooperate in encoding new memories? Phase synchronization of gamma-band electroencephalogram (EEG) oscillations (around 40 Hz) is a general mechanism of transiently connecting neural assemblies. We recorded depth-EEG from within the MTL of epilepsy patients performing a memorization task. Successful as opposed to unsuccessful memory formation was accompanied by an initial elevation of rhinal?hippocampal gamma synchronization followed by a later desynchronization, suggesting that effective declarative memory formation is accompanied by a direct and temporarily limited cooperation between both MTL substructures. [ABSTRACT FROM AUTHOR]

Presents information on studies conducted to detect verbal novelty within the human hippocampus, while highlighting studies conducted on animals. Reference to the importance of the human hippocampal; Methodology used to conduct study.

We found that personality characteristics are linked to dissociable connectivity streams in the human brain. Whereas fiber tracts between a subcortical network, including the hippocampus and amygdala, and the ventral striatum predicted individual differences in novelty seeking, tracts between prefrontal cortex and the striatum predicted individual differences in reward dependence. These findings suggest that the strength of limbic-striatal connectivity may, in part, underlie human personality traits. [ABSTRACT FROM AUTHOR]

Abstract The deficiency of declarative memory compared with waking state is an often overlooked characteristic of sleep. Here, we investigated whether rhinal–hippocampal coherence, an electrophysiological correlate of declarative memory formation, is significantly altered during sleep as compared with waking state. For this purpose, we analysed recordings of intracranial EEG activity during sleep obtained directly from within the medial temporal lobe in patients with unilateral temporal lobe epilepsy. We found a general reduction of rhinal–hippocampal EEG coherence during sleep compared with waking state, which was most pronounced within the upper gamma bands (average decrease up to 56%). The observed coherence changes clearly differ from findings reported for surface EEG data and thus appear to be specific for the medial temporal lobe. The decrease of rhinal–hippocampal EEG coherence from waking state towards sleep may yield an electrophysiological explanation for the sleep-related deficiency of declarative memory. [ABSTRACT FROM AUTHOR]

Abstract The hippocampus and the rhinal cortex, two substructures of the medial temporal lobe, together play a crucial role in human declarative memory formation. To investigate in detail the mechanism connecting these two structures transiently during memory formation we recorded depth EEG in epilepsy patients from within the hippocampus and the rhinal cortex. During this recording, patients performed a single-trial word list-learning paradigm with a free recall memory test following a distraction task. Rhinal–hippocampal EEG coherence and spectral power at both locations in the time interval up to 2 s after onset of word presentation were analysed in the frequency range 1–19 Hz. Successful as opposed to unsuccessful memory formation was associated with a general rhinal–hippocampal coherence enhancement, but without alterations in spectral power. Coherence increases in the theta range were correlated with the previously reported memory-related changes in rhinal–hippocampal gamma phase synchronization. This correlation may suggest an interaction of the two mechanisms during declarative memory formation. While theta coherence might be associated with slowly modulated coupling related to an encoding state, rhinal–hippocampal gamma synchronization may be more closely related to actual memory processes by enabling fast coupling and decoupling of the two structures. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Single neurons in the human MTL show abstract codes for addition and subtraction • Time-resolved decoding analysis shows a dynamic code in the parahippocampal cortex • The hippocampus shows a static code based on persistently rule-selective neurons • Different codes suggest different cognitive functions of MTL regions in arithmetic Kutter et al. demonstrate abstract and notation-independent codes for addition and subtraction in neuronal populations in the human medial temporal lobe (MTL). A dynamic code in the parahippocampal cortex contrasts with a static code in the hippocampus, suggesting different cognitive functions for these MTL regions in arithmetic. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondrial dysfunction has been identified as a potential cause of epileptic seizures and therapy-resistant forms of severe epilepsy. Thus, a broad variety of mutation in mitochondrial DNA or nuclear genes leading to the impairment of mitochondrial respiratory chain or of mitochondrial ATP synthesis has been associated with epileptic phenotypes. Additionally, with a variety of different methods impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon''s horn sclerosis and of animal models of temporal lobe epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca2+ homeostasis, their dysfunction strongly affects neuronal excitability and synaptic transmission, which is proposed to be highly relevant for seizure generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant temporal lobe epilepsy. Therefore, mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy. [Copyright &y& Elsevier]

Interactions between cells and extracellular matrix (ECM) molecules play a crucial role during brain development. The ECM glycoprotein tenascin-R (TN-R) has been implicated in the control of axon targeting, neural cell adhesion, migration and differentiation. Here, we have focused on the putative role of TN-R in chronic brain diseases involving increased neuronal excitability, as found in epilepsy. An episode of pilocarpine-induced status epilepticus (SE) led over a period of 3–30 days to neuron loss in the hippocampal hilus, CA3 and CA1 with reactive mossy fiber sprouting and astrogliosis in these regions. We found a focal up-regulation of granular TN-R immunoreactivity within the neuropil of segments of the CA3 pyramidal cell layer, the extent of this up-regulation paralleled the degree of pyramidal cell loss, mossy fiber sprouting and astrogliosis in these CA3 segments. In contrast, parvalbumin immunoreactivity and Wisteria floribundi agglutinin (WFA)-labeled perineuronal nets were reduced in CA3 segments with neuronal cell loss. The parallel development of increase in focal granular TN-R immunoreactivity, reactive mossy fiber sprouting and astrogliosis in CA3 implies a role for TN-R in axon targeting and synapse formation and/or in astrocytic targeting and interactions with the ECM during lesion-induced sprouting in the adult brain. [Copyright &y& Elsevier]

[Display omitted] • Eigenvalues of the Laplace–Beltrami operator on 3D mesh = Shape ("BrainPrint"). • Shape is complementary to volume in limbic encephalitis classification. • In lesional temporal lobe epilepsy shape is redundant to volume. • Shape explains memory performance in limbic encephalitis. Shape-based markers have entered the field of morphometric neuroimaging analysis as a second mainstay alongside conventional volumetric approaches. We aimed to assess the added value of shape description for the analysis of lesional and autoimmune temporal lobe epilepsy (TLE) focusing on hippocampus and amygdala. We retrospectively investigated MRI and clinical data from 65 patients with lesional TLE (hippocampal sclerosis (HS) and astrogliosis) and from 62 patients with limbic encephalitis (LE) with serologically proven autoantibodies. Surface reconstruction and volumetric segmentation were performed with FreeSurfer. For the shape analysis, we used BrainPrint , a tool that utilizes eigenvalues of the Laplace–Beltrami operator on triangular meshes to calculate intra-subject asymmetry. Psychometric tests of memory performance were ascertained, to evaluate clinical relevance of the shape descriptor. The potential benefit of shape in addition to volumetric information for classification was assessed by five-fold repeated cross validation and logistic regression. For the LE group, the best performing classification model consisted of a combination of volume and shape asymmetry (mean AUC = 0.728), the logistic regression model was significantly improved considering both modalities instead of just volume asymmetry. For lesional TLE, the best model only considered volumetric information (mean AUC = 0.867). Shape asymmetry of the hippocampus was largely associated with verbal memory performance only in LE patients (OR = 1.07, p = 0.02). For lesional TLE, shape description is robust, but redundant when compared to volumetric approaches. For LE, in contrast, shape asymmetry as a complementary modality significantly improves the detection of subtle morphometric changes and is further associated with memory performance, which underscores the clinical relevance of shape asymmetry as a novel imaging biomarker. [ABSTRACT FROM AUTHOR]

Abstract: Deeper semantic processing improves memory encoding of words. Neuroimaging studies suggest, that left-hemispheric structures, especially the left inferior frontal cortex and the left hippocampus mediate this effect. Therefore, we tested, whether chronic left hippocampal damage in epilepsy patients after selective amygdalohippocampectomy (SAH) diminishes the depth-of-processing effect in an incidental learning task. 16 patients after left SAH, 17 after right SAH and 15 healthy control subjects elaborated on word classification tasks under a non-semantic and two different semantic conditions. Recognition memory for the words was subsequently tested. Although memory in left SAH patients profited less from deeper semantic processing in terms of an absolute increase in the number of recognized words, the relative level of memory impairment compared to the two other groups was identical under the non-semantic and the semantic conditions. The results indicate that chronic left hippocampal damage affects recognition memory largely independent of semantic processing. [Copyright &y& Elsevier]

Abstract: The aim of the present study was to investigate whether forgetting is merely a passive process or whether it can also be caused by active suppression of memory contents. We investigated effects of directed forgetting by intracranial event-related potentials (ERPs) in 12 patients with mesial temporal lobe epilepsy. In a single-item directed forgetting paradigm, the patients were presented with words either followed by the instruction that this word has to-be-remembered (TBR) or to-be-forgotten (TBF). All patients were implanted with multicontact depth electrodes along the rhinal cortex and hippocampus as part of their presurgical evaluation. Patients recognized significantly less TBF than TBR words in a subsequent recognition test. In the hippocampus, TBF cues that caused subsequent forgetting were associated with decreased negative ERPs. In the rhinal cortex, TBF cues elicited a generally prolonged positivity, as compared to TBR cues. We interpret the decreased hippocampal ERPs following the TBF cues as an indication for an active suppression of hippocampal functions. The increased rhinal activity in response to the TBF cue might indicate an active involvement of this structure in the suppression of hippocampal memory formation. [Copyright &y& Elsevier]

Summary: The human brain is adept at anticipating upcoming events, but in a rapidly changing world, it is essential to detect and encode events that violate these expectancies. Unexpected events are more likely to be remembered than predictable events, but the underlying neural mechanisms for these effects remain unclear. We report intracranial EEG recordings from the hippocampus of epilepsy patients, and from the nucleus accumbens of depression patients. We found that unexpected stimuli enhance an early (187 ms) and a late (482 ms) hippocampal potential, and that the late potential is associated with successful memory encoding for these stimuli. Recordings from the nucleus accumbens revealed a late potential (peak at 475 ms), which increases in magnitude during unexpected items, but no subsequent memory effect and no early component. These results are consistent with the hypothesis that activity in a loop involving the hippocampus and the nucleus accumbens promotes encoding of unexpected events. [Copyright &y& Elsevier]

Abstract: Temporal lobe epilepsy with hippocampus sclerosis (HS) is the most frequent focal epilepsy and often refractory to anticonvulsant therapy. Secondary structural damage has been reported in several studies of temporal lobe epilepsy and unilateral hippocampal sclerosis. Applying diffusion tensor imaging (DTI) we investigated alterations in white matter following temporal lobe surgery in patients with medial temporal lobe epilepsy. We examined 40 patients who underwent surgery at our hospital for HS between 1996 and 2006 with diffusion tensor imaging (DTI). Images were obtained at a 3 T MRI scanner employing 60 gradient directions. Tract-based spatial statistics (TBSS), a novel voxel-based approach, was applied to analyze the data. Both patients with left- as well as right-sided surgery exhibited widespread degradation of fractional anisotropy (FA) in main fiber tracts not limited to the respective temporal lobe such as the uncinate fasciculus, the fronto-occipital fasciculus, the superior longitudinal fasciculus, the corpus callosum and the corticospinal tract on the respective hemisphere. Patients with left-hemispheric surgery showed more widespread affections ipsilaterally and also FA decrease in the contralateral inferior longitudinal fasciculus. DTI demonstrates widespread clusters of abnormal diffusivity and anisotropy in prominent white matter tracts linking mesial temporal lobe structures with other brain areas. Alterations in the ipsilateral mesial temporal lobe can be attributed to be a result of surgery, whereas extratemporal FA decrease is more likely the result of the underlying seizure disorder. [Copyright &y& Elsevier]

Abstract: Objective: The role of the hippocampus in sensory gating is unresolved as yet. The current study was conducted in order to examine the effects of hippocampal lesions on the function of auditory sensory gating. Methods: Epilepsy patients with unilateral and bilateral hippocampal sclerosis (HS) were investigated. Auditory-evoked potentials (AEPs) were recorded by multichannel scalp EEG in a double-click experiment. Gating was defined as the response decrease of the AEP components from 1st to 2nd click. Results: Diagnosis (left vs. right vs. bilateral HS) did not affect the amplitudes or gating of the P50, N100 or P200 components. However, diagnosis had an impact on the topography of the N100 component after its peak maximum: In right HS patients, the N100 was left-lateralized, while it was nearly symmetrically distributed in patients with left HS and right lateralized in patients with bilateral HS. Besides the N100, the topography of the P200 component was affected by diagnosis. Conclusions: Findings suggest that auditory activity, as reflected in the N100 and P200 components, is modulated by the hippocampus, but not sensory gating in its classical definition. Significance: Deficits in P50 gating in schizophrenia are unlikely to be explained by hippocampal deficits. [Copyright &y& Elsevier]

Abstract: Converging evidence indicates that the medial temporal lobe participates not only in memory but also in visual object processing. We investigated hippocampal contributions to visual object identification by recording event-related potentials directly from within the hippocampus during a visual object identification task with spatially filtered pictures of real objects presented at different levels of filtering. Hippocampal responses differentiated between identified and unidentified visual objects within a time window of 200–900ms after stimulus presentation: identified objects elicited a small negative component peaking around 300ms (hippocampal-N300) and a large positive component, around 650ms (hippocampal-P600), while the N300 was increased and the P600 was reduced in amplitude in response to unidentified objects. These findings demonstrate that the hippocampus proper contributes to the identification of visual objects discriminating from the very early between identified and unidentified meaningful visual objects. [Copyright &y& Elsevier]

Abstract: Amplitudes of the P3 recorded invasively from the medial temporal lobe (MTL-P3) have been reported to be reduced on the side of a mediotemporal epileptogenic focus. This reduction has been attributed to the massive cell loss within the hippocampus associated with hippocampal sclerosis. It has remained unclear how functional connectivity between the hippocampus and rhinal cortex, as well as within the hippocampus, is altered in hippocampal sclerosis. To investigate this issue, we analyzed to what extent stimulus-related phase-locking and power changes within the low-frequency range (2–30 Hz) and within the gamma band (32–48 Hz), as well as rhinal–hippocampal phase synchronization contribute to the averaged MTL-P3 potentials. Event-related responses were recorded via bilateral depth electrodes in epilepsy patients with unilateral hippocampal sclerosis, who performed a visual oddball experiment. On the contralateral (nonsclerotic) side, successful target detection was associated with an increase of power and phase locking of hippocampal activity in both the low-frequency range and in the gamma range. Besides, there were rhinal–hippocampal synchronization enhancements in the theta and gamma range. On the ipsilateral (sclerotic) side, the event-related power increase in the low-frequency range had almost disappeared, a finding likely to be explained by the loss of principle neurons. However, low-frequency phase-locking, rhinal–hippocampal synchronization, as well as event-related power changes in the gamma range persisted ipsilaterally, although there were differences in temporal and spectral characteristics. These findings support the hypothesis that functional connectivity between hippocampus and rhinal cortex, as well as intrahippocampal connectivity, are partially preserved in hippocampal sclerosis. [Copyright &y& Elsevier]

Presents research on the real-time tracking of memory formation in the human rhinal cortex and hippocampus. Experiment to identify neural correlations of memory formation with the use of intracerebral electrodes implanted in the brains of patients with temporal lobe epilepsy; Method; Suggestion that declarative memory formation is dissociable into subprocesses and sequentially organized within the median temporal lobe.