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1.  Serum from a Patient with GAD65 Antibody-Associated Limbic Encephalitis Did Not Alter GABAergic Neurotransmission in Cultured Hippocampal Networks 
Glutamate decarboxylase is an intracellular enzyme converting glutamate into GABA. Antibodies (abs) to its isoform GAD65 were described in limbic encephalitis and other neurological conditions. The significance of GAD65 abs for epilepsy is unclear, but alterations of inhibitory GABAergic neurotransmission may be involved. Here, we investigated the effects of the serum of a female patient suffering from GAD65 ab-associated LE on GABAA currents in cultured hippocampal networks.
Spontaneous or evoked post-synaptic GABAA currents were measured in cultured hippocampal neurons prepared from embryonic mice after 11–21 days in vitro using the patch-clamp technique in the whole-cell mode after incubation with serum of a healthy control or the LE-patient at a final concentration of 1% for 5–8 h.
Properties of miniature inhibitory post-synaptic currents were not different in cultures treated with control and LE-serum. Likewise, paired-pulse ratio of evoked GABAA currents as a measure of release probability was not different in both conditions. Evoked GABAA currents were significantly depressed during 10 Hz stimulation without significant differences between control and LE-serum treated cultures.
In our experimental paradigms, serum of a patient with confirmed GAD65 ab-associated LE had no apparent effect on GABAergic neurotransmission in murine-cultured hippocampal networks. These results challenge the view that the presence of GAD65 abs invariably compromise inhibitory network function.
PMCID: PMC4551833  PMID: 26379623
GAD65 antibodies; limbic encephalitis; GABAergic neurotransmission; hippocampal cultures; GABA(A) currents
2.  Treating a GAD65 Antibody-Associated Limbic Encephalitis with Basiliximab: A Case Study 
Antibodies (ABs) against the 65-kDa isoform of the intracellular enzyme glutamate decarboxylase (GAD65) have been found in limbic encephalitis (LE) and other neurological conditions. The direct significance of anti-GAD65-ABs for epilepsy is unclear. However, in histological preparations from biopsies of resective epilepsy surgeries, predominantly cytotoxic T-lymphocytes were detected making close contacts to neurons. Activated T-lymphocytes can, in turn, be selectively controlled by therapeutic interleukin-2 receptor Abs, such as basiliximab.
Case presentation
We report of a 25-year-old male patient with epilepsy since the age of 18 and displaying clinical signs of LE and a high titer of GAD65 ABs in cerebrospinal fluid (CSF) and serum. Monthly, repetitive, intravenous cortisone pulse therapies that were initially administered for 6 months failed to improve his condition. Subsequent flow-cytometry analysis of CSF showed especially an increased fraction of activated HLA-DR+ CD8+ T-lymphocytes (fCD8+TL) when compared to controls. Thus, a second, intravenous cortisone pulse therapy with an additional basiliximab dose of 20 mg/month was started. After 3 months, the fCD8+TL in the CSF normalized; after 6 months, the psychological impulse-control deficits normalized; and after 11 months the patient was seizure free. However, 7 weeks later, seizures and, later on, psychological deficits recurred and fCD8+TL was once again present in the CSF. Flumazenil PET, magnetic resonance imaging-volumetry, and neuropsychological changes during therapy are described.
The correlation of the fCD8+TL in the CSF with clinical and paraclinical measures of disease activity combined with the unambiguous response to basiliximab strongly argues in favor of the putative pathogenic role fCD8+TL in anti-GAD65 LE. The clinical relapse at the end of the observation period might be due to the formation of human anti-drug ABs, a well-known complication of therapy with chimeric ABs.
PMCID: PMC4522569  PMID: 26284025
limbic encephalitis; GAD65; epilepsy; basiliximab; cytotoxic T lymphocytes
3.  How generalised are secondarily “generalised” tonic–clonic seizures? 
In clinical practice, epileptic seizures with focal onset and subsequent generalised motor involvement are referred to as secondarily generalised seizures. The purpose of this study was to investigate the degree of electrophysiological generalisation in seizures that are clinically secondarily generalised. Intracranial EEG recordings of secondarily generalised tonic–clonic seizures were visually and quantitatively analysed for the presence of epileptiform activity. In 24 (26%) of 93 seizures recorded from 17 (27%) of 64 patients, intracranial EEG channels were found that never recorded epileptiform activity during secondarily generalised tonic–clonic seizures. Our results demonstrate that seizures that are secondarily generalised clinically are not always generalised electrophysiologically. This may have therapeutic implications.
PMCID: PMC2117860  PMID: 17237141
4.  Burden Analysis of Rare Microdeletions Suggests a Strong Impact of Neurodevelopmental Genes in Genetic Generalised Epilepsies 
PLoS Genetics  2015;11(5):e1005226.
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
Author Summary
Epilepsy affects about 4% of the general population during lifetime. The genetic generalised epilepsies (GGEs) represent the most common group of epilepsies with predominant genetic aetiology, accounting for 20% of all epilepsies. Despite their strong heritability, the genetic basis of the majority of patients with GGE remains elusive. Genomic microdeletions constitute a significant source of genetic risk factors for epilepsies. The present genome-wide burden analysis in 1,366 European patients with GGE and 5,234 ancestry-matched controls explored the role of large and rare microdeletions (size ≥ 400 kb, frequency < 1%) in the complex genetic architecture of common GGE syndromes. Our results revealed a 2-fold excess of microdeletions in GGE patients relative to the population controls, 2) a 7-fold increased burden for known hotspot microdeletions (15q11.2, 15q13.3, 16p13.11, 22q11.2) previously associated with a wide range of neurodevelopmental disorders, and 3) a more than 4-fold enrichment of microdeletions carrying a gene implicated in neurodevelopmental disorders. Our findings reinforce emerging evidence that genes affected by microdeletions in GGE patients have a strong impact in fundamental neurodevelopmental processes and dissect novel candidate genes involved in epileptogenesis.
PMCID: PMC4423931  PMID: 25950944
5.  Prolonged atrial fibrillation following generalised tonic-clonic seizures 
We describe two male patients with focal epilepsy in whom transitory episodes of atrial fibrillation (AF) lasting for up to 25 hours were detected in the context of generalised tonic-clonic seizures (GTCS). In five of seven previously published cases of transitory AF associated with epileptic seizures, AF was also associated with GTCS, suggesting a pathophysiological link via GTCS-related increase in sympathetic tone and release of catecholamines. Importantly, AF increases the risk of thromboembolic cerebral ischemia, prompting the question of whether antithrombotic preventive treatment should be initiated in people with pharmacoresistant epilepsy and prolonged peri-ictal AF. Furthermore, AF can considerably impair cardiac output and may, via this mechanism, contribute to the risk of sudden unexpected death in epilepsy following GTCS.
PMCID: PMC4104675  PMID: 22698381
Sudden unexpected death in epilepsy; cardiac arrhythmia; atrial fibrillation; chronic epilepsy
6.  Postictal generalized EEG suppression 
Neurology  2013;81(14):1252-1256.
To determine the consistency and facilitating cofactors of postictal generalized EEG suppression (PGES) of >20 seconds after convulsive seizures (CS), a suggested predictor of sudden unexpected death in epilepsy risk.
We retrospectively reviewed video-EEG data of people with ≥2 recorded CS. Presence and duration of PGES were assessed by 2 independent observers blinded to patient status. Intraindividual consistency of PGES >20 seconds was determined and correlations with clinical characteristics were analyzed after correction for individual effects and the varying number of seizures.
One hundred fifty-four seizures in 59 people were analyzed. PGES >20 seconds was found in 37 individuals (63%) and 57 (37%) of CS. The proportion of persons in whom PGES occurred consistently (presence or absence of PGES >20 seconds in all CS) was lower in those with more CS. PGES of >20 seconds was more frequent in seizures arising from sleep (odds ratio 3.29, 95% confidence interval 1.21–8.96) and when antiepileptic medication was tapered (odds ratio 4.80, 95% confidence interval 1.27–18.14).
Apparent PGES consistency was less frequent in people with more CS recorded, suggesting that PGES is an inconsistent finding in any one individual. Thus, we believe that PGES >20 seconds is not a reliable predictor of sudden unexpected death in epilepsy. Sleep and antiepileptic drug reduction appear to facilitate the occurrence of PGES.
PMCID: PMC3795608  PMID: 23966251
7.  A reward prediction error for charitable donations reveals outcome orientation of donators 
The motives underlying prosocial behavior, like charitable donations, can be related either to actions or to outcomes. To address the neural basis of outcome orientation in charitable giving, we asked 33 subjects to make choices affecting their own payoffs and payoffs to a charity organization, while being scanned by functional magnetic resonance imaging (fMRI). We experimentally induced a reward prediction error (RPE) by subsequently discarding some of the chosen outcomes. Co-localized to a nucleus accumbens BOLD signal corresponding to the RPE for the subject's own payoff, we observed an equivalent RPE signal for the charity's payoff in those subjects who were willing to donate. This unique demonstration of a neuronal RPE signal for outcomes exclusively affecting unrelated others indicates common brain processes during outcome evaluation for selfish, individual and nonselfish, social rewards and strongly suggests the effectiveness of outcome-oriented motives in charitable giving.
PMCID: PMC3575724  PMID: 22198972
charitable donations; reward processing; social preferences; functional magnetic resonance imaging (fMRI); nucleus accumbens (NAc)
8.  Cliniconeuropathologic correlations show astroglial albumin storage as a common factor in epileptogenic vascular lesions 
Epilepsia  2012;53(3):539-548.
Intracerebral vascular malformations including cavernous angiomas (CAs) and arteriovenous malformations (AVMs) are an important cause of chronic pharmacoresistant epilepsies. Little is known about the pathogenetic basis of epilepsy in patients with vascular malformations. Intracerebral deposits of iron-containing blood products have been generally regarded as responsible for the strong epileptogenic potential of CAs. Here, we have analyzed whether blood–brain barrier (BBB) dysfunction and subsequent astrocytic albumin uptake, recently described as critical trigger of focal epilepsy, represent pathogenetic factors in vascular lesion–associated epileptogenesis.
We examined the correlation between hemosiderin deposits, albumin accumulation, and several clinical characteristics in a series of 80 drug-refractory epilepsy patients with CAs or AVMs who underwent surgical resection. Analysis of clinical parameters included gender, age of seizure onset, epilepsy frequency, duration of epilepsy before surgery, and postoperative seizure outcome classification according to Engel class scale. Hemosiderin deposits in the adjacent brain tissue of the vascular lesion were semiquantitatively analyzed. Fluorescent double-immunohistochemistry using GFAP/albumin costaining was performed to study albumin extravasation.
Key Findings
Our results suggest that a shorter duration of preoperative epilepsy is correlated with significantly better postsurgical outcome (p < 0.05), whereas no additional clinical or neuropathologic parameter correlated significantly with the postsurgical seizure situation. Intriguingly, we observed strong albumin immunoreactivity within the vascular lesion and in perilesional astrocytes (57.65 ± 4.05%), but not in different control groups.
Our present data on albumin uptake in brain tissue adjacent to AVMs and CAs suggests BBB dysfunction and accumulation of albumin within astrocytes as a new pathologic feature potentially associated with the epileptogenic mechanism for vascular lesions and provides novel therapy perspectives for antiepileptogenesis in affected patients.
PMCID: PMC3669690  PMID: 22372630
Epilepsy; Vascular malformation; Cavernoma; Albumin; Hemosiderin
9.  Ictal Modulation of Cardiac Repolarization, but Not of Heart Rate, Is Lateralized in Mesial Temporal Lobe Epilepsy 
PLoS ONE  2013;8(5):e64765.
Human and animal studies provided controversial data on asymmetric cortical representation of cardiac function, which may partially be due to different study designs and inter-individual variability. Here, we investigated whether seizure-related changes in heart rate (HR) and cardiac repolarization depend on the side of seizure-activity in people with mesial temporal lobe epilepsy (mTLE).
To account for inter-individual variability, EEG and ECG data were reviewed from patients with medically refractory mTLE undergoing pre-surgical video-EEG telemetry with at least 2 seizures arising from each hippocampus as assessed by bilateral hippocampal depths electrodes. RR and QT intervals were determined at different timepoints using a one-lead ECG. QT intervals were corrected for HR (QTc) using 4 established formulas.
Eighty-two seizures of 15 patients were analyzed. HR increased by ∼30% during hippocampal activity irrespective of the side (p = 0.411). QTc intervals were lengthened to a significantly greater extent during left hippocampal seizures (e.g. difference of QT intervals between preictal and ictal state using Bazett’s formula; left side 32.0±5.3 ms, right side 15.6±7.7 ms; p = 0.016). Abnormal QTc prolongation occurred in 7 of 41 left hippocampal seizures of 4 patients, and only in 2 of 37 right hippocampal seizures of 2 patients.
Seizure-related modulation of cardiac repolarization, but not of HR, appears to depend on the side of ictal activity, strengthening the hypothesis of asymmetric cerebral representation of cardiac function. The clinical relevance of this is unclear, but may indicate an increased risk of abnormal ictal QT prolongation in people with left mTLE.
PMCID: PMC3669418  PMID: 23741389
10.  Neural responses to advantageous and disadvantageous inequity 
In this paper we study neural responses to inequitable distributions of rewards despite equal performance. We specifically focus on differences between advantageous inequity (AI) and disadvantageous inequity (DI). AI and DI were realized in a hyperscanning functional magnetic resonance imaging (fMRI) experiment with pairs of subjects simultaneously performing a task in adjacent scanners and observing both subjects' rewards. Results showed (1) hypoactivation of the ventral striatum (VS) under DI but not under AI; (2) inequity induced activation of the right dorsolateral prefrontal cortex (DLPFC) that was stronger under DI than under AI; (3) correlations between subjective evaluations of AI evaluation and bilateral ventrolateral prefrontal and left insular activity. Our study provides neurophysiological evidence for different cognitive processes that occur when exposed to DI and AI, respectively. One possible interpretation is that any form of inequity represents a norm violation, but that important differences between AI and DI emerge from an asymmetric involvement of status concerns.
PMCID: PMC3370647  PMID: 22701414
equity norm; social preferences; functional magnetic resonance imaging (fMRI); ventral striatum
11.  What is Depression in Epilepsy? 
PMCID: PMC3232452  PMID: 22162974
12.  Ventromedial Prefrontal Cortex Activation Is Associated with Memory Formation for Predictable Rewards 
PLoS ONE  2011;6(2):e16695.
During reinforcement learning, dopamine release shifts from the moment of reward consumption to the time point when the reward can be predicted. Previous studies provide consistent evidence that reward-predicting cues enhance long-term memory (LTM) formation of these items via dopaminergic projections to the ventral striatum. However, it is less clear whether memory for items that do not precede a reward but are directly associated with reward consumption is also facilitated. Here, we investigated this question in an fMRI paradigm in which LTM for reward-predicting and neutral cues was compared to LTM for items presented during consumption of reliably predictable as compared to less predictable rewards. We observed activation of the ventral striatum and enhanced memory formation during reward anticipation. During processing of less predictable as compared to reliably predictable rewards, the ventral striatum was activated as well, but items associated with less predictable outcomes were remembered worse than items associated with reliably predictable outcomes. Processing of reliably predictable rewards activated the ventromedial prefrontal cortex (vmPFC), and vmPFC BOLD responses were associated with successful memory formation of these items. Taken together, these findings show that consumption of reliably predictable rewards facilitates LTM formation and is associated with activation of the vmPFC.
PMCID: PMC3033899  PMID: 21326612
13.  15q13.3 microdeletions increase risk of idiopathic generalized epilepsy 
Nature genetics  2009;41(2):160-162.
We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 × 10−8). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.
PMCID: PMC3026630  PMID: 19136953
14.  Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies 
Brain  2009;133(1):23-32.
Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8–13.2; χ2 = 26.7; 1 degree of freedom; P = 2.4 × 10−7). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8–13.2; P = 4.2 × 10−4) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3–74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
PMCID: PMC2801323  PMID: 19843651
idiopathic generalized epilepsy; microdeletions; association; genetics
15.  Identification of Preseizure States in Epilepsy: A Data-Driven Approach for Multichannel EEG Recordings 
The retrospective identification of preseizure states usually bases on a time-resolved characterization of dynamical aspects of multichannel neurophysiologic recordings that can be assessed with measures from linear or non-linear time series analysis. This approach renders time profiles of a characterizing measure – so-called measure profiles – for different recording sites or combinations thereof. Various downstream evaluation techniques have been proposed to single out measure profiles that carry potential information about preseizure states. These techniques, however, rely on assumptions about seizure precursor dynamics that might not be generally valid or face the statistical problem of multiple testing. Addressing these issues, we have developed a method to preselect measure profiles that carry potential information about preseizure states, and to identify brain regions associated with seizure precursor dynamics. Our data-driven method is based on the ratio S of the global to local temporal variance of measure profiles. We evaluated its suitability by retrospectively analyzing long-lasting multichannel intracranial EEG recordings from 18 patients that included 133 focal onset seizures, using a bivariate measure for the strength of interactions. In 17/18 patients, we observed S to be significantly correlated with the predictive performance of measure profiles assessed retrospectively by means of receiver-operating-characteristic statistics. Predictive performance was higher for measure profiles preselected with S than for a manual selection using information about onset and spread of seizures. Across patients, highest predictive performance was not restricted to recordings from focal areas, thus supporting the notion of an extended epileptic network in which even distant brain regions contribute to seizure generation. We expect our method to provide further insight into the complex spatial and temporal aspects of the seizure generating process.
PMCID: PMC3133837  PMID: 21779241
epileptic networks; epilepsy; synchronization; EEG; seizure prediction; seizure precursor
16.  Distinct patterns of mitochondrial genome diversity in bonobos (Pan paniscus) and humans 
We have analyzed the complete mitochondrial genomes of 22 Pan paniscus (bonobo, pygmy chimpanzee) individuals to assess the detailed mitochondrial DNA (mtDNA) phylogeny of this close relative of Homo sapiens.
We identified three major clades among bonobos that separated approximately 540,000 years ago, as suggested by Bayesian analysis. Incidentally, we discovered that the current reference sequence for bonobo likely is a hybrid of the mitochondrial genomes of two distant individuals. When comparing spectra of polymorphic mtDNA sites in bonobos and humans, we observed two major differences: (i) Of all 31 bonobo mtDNA homoplasies, i.e. nucleotide changes that occurred independently on separate branches of the phylogenetic tree, 13 were not homoplasic in humans. This indicates that at least a part of the unstable sites of the mitochondrial genome is species-specific and difficult to be explained on the basis of a mutational hotspot concept. (ii) A comparison of the ratios of non-synonymous to synonymous changes (dN/dS) among polymorphic positions in bonobos and in 4902 Homo sapiens mitochondrial genomes revealed a remarkable difference in the strength of purifying selection in the mitochondrial genes of the F0F1-ATPase complex. While in bonobos this complex showed a similar low value as complexes I and IV, human haplogroups displayed 2.2 to 7.6 times increased dN/dS ratios when compared to bonobos.
Some variants of mitochondrially encoded subunits of the ATPase complex in humans very likely decrease the efficiency of energy conversion leading to production of extra heat. Thus, we hypothesize that the species-specific release of evolutionary constraints for the mitochondrial genes of the proton-translocating ATPase is a consequence of altered heat homeostasis in modern humans.
PMCID: PMC2942848  PMID: 20813043
17.  Graded Effects of Social Conformity on Recognition Memory 
PLoS ONE  2010;5(2):e9270.
Previous studies have shown that the opinion of confederates in a group influences recognition memory, but inconsistent results have been obtained concerning the question of whether recognition of items as old and new are affected similarly, possibly because only one or two confederates are present during the recognition phase. Here, we present data from a study where recognition of novel faces was tested in the presence of four confederates. In a long version of this experiment, recognition of items as old and new was similarly affected by group responses. However, in the short version, recognition of old items depended proportionally on the number of correct group responses, while rejection of new items only decreased significantly when all confederates gave an incorrect response. These findings indicate that differential effects of social conformity on recognition of items as old and new occur in situations with an intermediate level of group pressure.
PMCID: PMC2822843  PMID: 20174641
18.  Nuclei accumbens phase synchrony predicts decision-making reversals following negative feedback 
The nucleus accumbens plays a key role in reinforcement-guided behaviors. Here we report that electrophysiological oscillatory phase synchrony between the two nuclei accumbens may play a crucial role in using negative feedback to guide decision-making. We recorded local field potentials from the human nucleus accumbens and the medial frontal cortex (via surface EEG) from patients who had deep-brain-stimulation electrodes implanted. Patients performed a reversal learning task in which they decided whether to alter their decision strategy following monetary losses. Strategy switches following losses were preceded by enhanced theta (4–8 Hz) phase synchrony between the nuclei accumbens, and a break-down of gamma (20–80 Hz)—alpha (8–12 Hz) coupling. Further, the strength of the inter-site phase synchrony predicted response time adjustments in the subsequent trial. These findings suggest that a neural network including the nucleus accumbens bilaterally becomes functionally connected via theta phase synchrony to signal the need to adjust behavior.
PMCID: PMC2725399  PMID: 19515927
nucleus accumbens; reinforcement learning; reward; oscillation; phase coherence; cross-frequency coupling
19.  Distinct regional atrophy in the corpus callosum of patients with temporal lobe epilepsy 
Brain : a journal of neurology  2007;130(Pt 12):3149-3154.
We analysed the influence of mesial temporal lobe epilepsy on the thickness of the corpus callosum (CC) in a large sample of well-characterized patients (n = 96) and healthy controls (n = 28). In particular, we investigated whether callosal structures are differentially affected depending on the affected hemisphere and age of epilepsy onset. Overall, we observed that epilepsy is associated with a decreased thickness in posterior callosal regions. Patients with an early onset, especially patients with left onset, additionally exhibited a smaller callosal thickness in more anterior and midbody regions. These findings may reflect non-specific as well as specific effects of temporal lobe epilepsy on CC development and interhemispheric connectivity.
PMCID: PMC2770440  PMID: 17728360
corpus callosum; temporal lobe epilepsy; MRI
20.  Hippocampal event-related potentials to tone duration deviance in a passive oddball paradigm in humans 
NeuroImage  2007;37(1):274-281.
The mismatch negativity (MMN), a component of event-related potentials (ERPs), is assumed to reflect a pre-attentive auditory discrimination process. Although an involvement of hippocampal structures in deviance detection was shown in animal experiments, invasive recordings in humans have not been able to provide such an evidence so far. In the current study, ERPs were recorded from intrahippocampal and scalp electrodes in 16 epilepsy patients. Stimulation consisted of trains of six tones, with one tone deviating in duration (100 vs. 50 ms). In the rhinal cortex, ERPs elicited by deviants were larger in amplitude than those of standards (around 200 ms). The rhinal activation was succeeded by a long-lasting hippocampal ERP component (around 350 ms). However, in contrast to the rhinal activation, hippocampal activation was also elicited by the 1st stimuli of the train and might, therefore, be related more to salience detection than to deviance detection. The current study provides evidence that the MMN is part of a multistage comparison process and that the rhinal cortex is part of its underlying cortical network.
PMCID: PMC1992525  PMID: 17560796
auditory evoked potentials; attention; electrocorticography
21.  Enhancement of Neocortical-Medial Temporal EEG Correlations during Non-REM Sleep 
Neural Plasticity  2008;2008:563028.
Interregional interactions of oscillatory activity are crucial for the integrated processing of multiple brain regions. However, while the EEG in virtually all brain structures passes through substantial modifications during sleep, it is still an open question whether interactions between neocortical and medial temporal EEG oscillations also depend on the state of alertness. Several previous studies in animals and humans suggest that hippocampal-neocortical interactions crucially depend on the state of alertness (i.e., waking state or sleep). Here, we analyzed scalp and intracranial EEG recordings during sleep and waking state in epilepsy patients undergoing presurgical evaluation. We found that the amplitudes of oscillations within the medial temporal lobe and the neocortex were more closely correlated during sleep, in particular during non-REM sleep, than during waking state. Possibly, the encoding of novel sensory inputs, which mainly occurs during waking state, requires that medial temporal dynamics are rather independent from neocortical dynamics, while the consolidation of memories during sleep may demand closer interactions between MTL and neocortex.
PMCID: PMC2430382  PMID: 18566693
22.  Epilepsy research: a window onto function and dysfunction of the human brain 
As one of the most common neurological disorders, epilepsy has devastating behavioral, social, and occupational consequences and is associated with accumulating brain damage and neurological deficits. Epilepsy comprises a large number of syndromes, which vary greatly respect to their etiology and clinical features, but share the characteristic clinical hallmark of epilepsy recurrent spontaneous seizures. Research aimed at understanding the genetic, molecular, and cellular basis of epilepsy has to integrate various research approaches and techniques ranging from clinical expertise, functional analyses of the system and cellular levels, both in human subjects and rodent models of epilepsy, to human and mouse genetics. This knowledge may then be developed into novel treatment options with better control of seizures andlor fewer side effects. In addition, the study of epilepsy has frequently shed light on basic mechanisms underlying the function and dysfunction of the human brain.
PMCID: PMC3181865  PMID: 18472480
epilepsy research; epilepsy model; human genetics; transgenic mouse; pharmacoresistance; phannacogenoinics
23.  Reward Expectation Modulates Feedback-Related Negativity and EEG Spectra 
NeuroImage  2007;35(2):968-978.
The ability to evaluate outcomes of previous decisions is critical to adaptive decision-making. The feedback-related negativity (FRN) is an event-related potential (ERP) modulation that distinguishes losses from wins, but little is known about the effects of outcome probability on these ERP responses. Further, little is known about the frequency characteristics of feedback processing, for example, event-related oscillations and phase synchronizations. Here, we report an EEG experiment designed to address these issues. Subjects engaged in a probabilistic reinforcement learning task in which we manipulated, across blocks, the probability of winning and losing to each of two possible decision options. Behaviorally, all subjects quickly adapted their decision-making to maximize rewards. ERP analyses revealed that the probability of reward modulated neural responses to wins, but not to losses. This was seen both across blocks as well as within blocks, as learning progressed. Frequency decomposition via complex wavelets revealed that EEG responses to losses, compared to wins, were associated with enhanced power and phase coherence in the theta frequency band. As in the ERP analyses, power and phase coherence values following wins but not losses were modulated by reward probability. Some findings between ERP and frequency analyses diverged, suggesting that these analytic approaches provide complementary insights into neural processing. These findings suggest that the neural mechanisms of feedback processing may differ between wins and losses.
PMCID: PMC1868547  PMID: 17257860
reward prediction error; ERP; decision-making; EEG oscillations; reinforcement learning
24.  Recombination of mitochondrial DNA detected in skeletal muscle of individuals with multiple mitochondrial DNA heteroplasmy 
Nature genetics  2005;37(8):873-877.
Experimental evidence for human mitochondrial DNA (mtDNA) recombination was recently obtained in one exceptional individual with paternal inheritance of mtDNA1 and in an in vitro cell culture system2. Whether mtDNA recombination is a common event in humans remained to be elucidated. To detect mtDNA recombination in human skeletal muscle, we have analyzed the distribution of alleles in individuals with multiple mtDNA heteroplasmy using single-cell PCR and allele-specific PCR. In ten out of ten individuals who harbored a heteroplasmic D-loop mutation and a distantly located tRNA point mutation or a large deletion, we observed a mixture of four allelic combinations (tetraplasmy), a hallmark of recombination. Reassuringly, 12 out of 14 individuals with closely located heteroplasmic D-loop mutation pairs contained a mixture of only three types of mitochondrial genomes (triplasmy), consistent with the absence of recombination between adjacent markers. These findings indicate that mtDNA recombination is common in human skeletal muscle.
PMCID: PMC1444756  PMID: 16025113
25.  Independent Delta/Theta Rhythms in the Human Hippocampus and Entorhinal Cortex 
Theta oscillations in the medial temporal lobe (MTL) of mammals are involved in various functions such as spatial navigation, sensorimotor integration, and cognitive processing. While the theta rhythm was originally assumed to originate in the medial septum, more recent studies suggest autonomous theta generation in the MTL. Although coherence between entorhinal and hippocampal theta activity has been found to influence memory formation, it remains unclear whether these two structures can generate theta independently. In this study we analyzed intracranial electroencephalographic (EEG) recordings from 22 patients with unilateral hippocampal sclerosis undergoing presurgical evaluation prior to resection of the epileptic focus. Using a wavelet-based, frequency-band-specific measure of phase synchronization, we quantified synchrony between 10 different recording sites along the longitudinal axis of the hippocampal formation in the non-epileptic brain hemisphere. We compared EEG synchrony between adjacent recording sites (i) within the entorhinal cortex, (ii) within the hippocampus, and (iii) between the hippocampus and entorhinal cortex. We observed a significant interregional gap in synchrony for the delta and theta band, indicating the existence of independent delta/theta rhythms in different subregions of the human MTL. The interaction of these rhythms could represent the temporal basis for the information processing required for mnemonic encoding and retrieval.
PMCID: PMC2525973  PMID: 18958204
medial temporal lobe; intracranial EEG; oscillations; synchronization; wavelet; phase precession

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