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An investigation of traumatic life events and obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD), like most other psychiatric disorders, is suspected of being influenced by an interaction between life events and genes, both with regard to onset and course of illness. To date, no specific genes have been identified as playing a frequent role, and only a relatively few empirical studies have assessed the association between stressful life events (SLEs) and OCD. The present study builds on past research by examining the potential contributions from traumatic life events (TLEs) on the severity and symptom features in 265 individuals with Structured Clinical Interview for DSM-IV (SCID)-diagnosed OCD. Of these participants 54% endorsed having experienced at least one TLE in their life time. The presence of one or more TLEs was associated with increased OCD symptom severity. This relationship remained significant despite controlling for key variables including age, OCD age-of-onset, comorbidity, and depressive symptoms. In addition, obsessions/checking and symmetry/ordering were two of four symptom factors that were specifically associated with the occurrence of TLEs. These results are generally supportive of a pathoplastic relationship between TLEs and OCD symptomatology and thus suggest the need for greater systematic consideration of life stresses in research focused on the nature and treatment of OCD.

Adult↗

Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway.

Switching specific patterns of gene repression and activation in response to precise temporal/spatial signals is critical for normal development. Here we report a pathway in which induction of CaMKIIdelta triggers an unexpected switch in the function of the HES1 transcription factor from a TLE-dependent repressor to an activator required for neuronal differentiation. These events are based on activation of the poly(ADP-ribose) polymerase1 (PARP-1) sensor component of the groucho/TLE-corepressor complex mediating dismissal of the corepressor complex from HES1-regulated promoters. In parallel, CaMKIIdelta mediates a required phosphorylation of HES1 to permit neurogenic gene activation, revealing the ability of a specific signaling pathway to modulate both the derepression and the subsequent coactivator recruitment events required for transcriptional activation of a neurogenic program. The identification of PARP-1 as a regulated promoter-specific exchange factor required for activation of specific neurogenic gene programs is likely to be prototypic of similar molecular mechanisms.

Animals↗

Electrical brain-stimulation paradigm for estimating the seizure onset site and the time to ictal transition in temporal lobe epilepsy.

OBJECTIVE: To explore and validate a novel stimulation and analysis paradigm proposed to monitor spatial distribution and temporal changes of the excitability state in patients with temporal lobe epilepsy (TLE). METHODS: We use intermittent pulse stimulation in the frequency range 10-20Hz. A quantitative measure of spectral phase de-modulation, the relative phase clustering index (rPCI) was applied to the evoked EEG signals, measured from electrodes implanted in the hippocampal formation. RESULTS: We found that in the interictal periods, high values of rPCI recorded from specific sites were correlated with the most probable seizure onset sites (SOS). Furthermore we found that high values of rPCI from certain locations correlated with shorter time intervals to the next seizure. CONCLUSIONS: Our clinical findings indicate that although the precise moment of ictal transitions is in general unpredictable, it may be possible to estimate the probability of occurrence of some epileptic seizures. SIGNIFICANCE: The use of the rPCI for probabilistic forecasting of upcoming epileptic seizures is warranted. rPCI measurements may be used to guide interventions with the aim of modifying local tissue excitability that ultimately might prevent ictal transitions.

Brain Mapping↗

Patterns of dentate granule cell responses to perforant path stimulation in epileptic mice with granule cell dispersion.

In adult mice, intrahippocampal administration of kainic acid induces a structural modification of the granule cell layer reminiscent of granule cell dispersion (GCD) seen in humans with temporal lobe epilepsy. We tested that GCD might be involved in the patterns of granule cell responses to perforant path stimulation by recording field potentials in vivo after kainic acid-induced status epilepticus until the phase of chronic seizure activity in presence of GCD or after its alteration by K252a co-treatment, an inhibitor of tyrosine kinase activities. Stimulation triggered bursts of multiple population spikes, the number of which progressively increased with time whereas their amplitude decreased in parallel with the progressive decrease in granule cell density. The population spike threshold was reached for a lower excitatory synaptic drive than in controls, as assessed by the initial slope of the field excitatory post-synaptic potential. This indicates that, for identical synaptic responses, granule cells were closer to the firing threshold. Fast inhibition, assessed by paired pulse stimulation, was compromised immediately after the initial status epilepticus, consistent with the rapid loss of most hilar cells. Neither the epileptic course nor the epileptiform responses of the granule cells were modified and manipulation by alteration following GCD manipulation while granule cell neuropeptide-Y immunostaining was substantially decreased. In this mouse model of TLE, granule cells display a progressive increase in epileptiform responses to afferent input until the occurrence of spontaneous seizures. The population spike amplitude decreases in parallel with GCD while the granule cell excitability is enhanced. Consequently, data from field potentials in epilepsy experiments should be interpreted with care, taking into account the possible variations in the neuronal density in the recorded area.

Action Potentials↗

Selective memory impairment for public events in a patient with left temporal lobe epilepsy.

Highly selective memory impairment for public events was demonstrated in a patient (JR), who suffered from temporal lobe epilepsy (TLE). We successfully trained JR's memory for a set of news events and discuss, on those bases, the characteristics of news events processing that may have contributed to its increased vulnerability relative to autobiographical memory (AbM).

Epilepsy, Temporal Lobe↗

Language activation distributions revealed by fMRI in post-operative epilepsy patients: differences between left- and right-sided resections.

OBJECTIVE: To reveal differences of cerebral activation related to language functions in post-operative temporal lobe epilepsy (TLE) patients. METHODS: Right (RTL) and left temporal lobe (LTL) resected patients, and healthy controls were studied using functional magnetic resonance imaging (fMRI). Only patients with complete left-hemispheric language dominance according to the intracarotid amytal procedure (IAP) were included. Language-related activations were evoked by performing word generation and text reading language tasks. Activation lateralization and temporo-frontal distribution effects were analysed. RESULTS: For word generation, only LTL patients showed reduced left lateralized activation compared to controls, due to a decrease in activation in the left prefrontal cortex and an increase in the right prefrontal cortex. For reading, the left-hemispheric lateralization in RTL patients increased because of enhanced activity in the left prefrontal cortex, whereas for LTL patients the activation became bilaterally distributed over the temporal lobes. Lateralization results between pre-operative IAP and post-operative fMRI were highly discordant. Significant temporo-frontal distribution changes manifested from the reading but not from the word generation task. CONCLUSION: The cerebral language representation in post-operative LTL epilepsy patients is more bi-hemispherically lateralized than in controls and RTL patients. Post-operative temporo-frontal and interhemispheric redistribution effects, involving contralateral homologous brain areas, are suggested to contribute to the cerebral reorganisation of language function.

Adult↗

Relative localizing value of amygdalo-hippocampal MR biometry in temporal lobe epilepsy.

OBJECTIVES: The aims of the study were (i) to examine the localizing value of three MRI quantitative modalities (qMRI) currently used for the analysis of the hippocampus and amygdala in the context of pre-surgical screening and (ii) to propose a step-by-step protocol based on the sensitivity and performance of the different MR techniques. METHODS: Ninety-two adults with chronic mesial temporal lobe epilepsy (TLE) of which 28 underwent amygdalo-hippocampal resection, and 34 age-matched controls were included in the study. High-resolution qMRI was performed at 1.5 T, including a tilted T1-weighted 3D-dataset for volumetry and four-echoes T2 relaxometry (both for hippocampus and amygdala quantifications) and multi-voxel spectroscopy [NAA/(Cho+Cre)] (exclusively in the hippocampus). Individual qMRI data were compared with electroencephalography regarding the localization of the epileptogenic area, with the neuropathological data and with postoperative outcome. MRI pathology was defined based on 99% confidence ellipses. Ten controls were used to assess the quantitative MRI intra- and inter-observer variability for all variables. RESULTS: Volumetric measurements revealed unilateral damage in 77% of the patients, T2-relaxometry in 64% and spectroscopy in 53%. Additional measurements of the amygdalae (T2-relaxometry) allowed us to localize pathology that coexists with that of the hippocampus in 34%, and isolated unilateral amygdala damage in 8% of patients. Volumetry and T2-relaxometry (not spectroscopy) were associated with postoperative outcome, but accurate predictive models were computed based on hippocampal measures only. At least at 1-year follow-up, volumetry predicts outcome correctly in 100% of the cases, whilst T2-relaxometry classified 96.4% (27/28) of these patients. All operated patients had hippocampal sclerosis. CONCLUSIONS: Hippocampal structural damage is equivocally depicted by spectroscopy. For diagnostic and pre-operative evaluation, hippocampal volumetry and T2-relaxometry provide maximal accuracy. Amygdala quantifications are irrelevant in the pre-operative evaluation but may be useful for diagnostic purposes. Of the three qMRI modalities tested, T2-relaxometry provided the best balance between diagnosis accuracy and time-efficiency to lateralize a sclerotic lesion on the majority of the patients. Cases that remain undecided after T2-relaxometry may benefit from additional measurements based on hippocampal volumetry.

Adolescent↗

MRI compatible electrodes for the induction of amygdala kindling in rats.

The rat electrical kindling model has been widely utilized in epilepsy research. This study aimed to identify the optimum "MRI compatible" bipolar stimulating and recording electrodes to enable serial MRI acquisition in this model. Two types of custom-made electrodes (gold and carbon) were compared with commercial platinum-iridium alloy electrodes for suitability based on size, effect on image quality and kindling induction. The custom-made gold electrodes, based on these parameters, were found to be most suitable. These electrodes enable the study of epileptogenesis utilizing MRI in this model of temporal lobe epilepsy (TLE).

Amygdala↗

A volumetric MRI study of the hippocampus and the parahippocampal region after unilateral medial temporal lobe resection.

Segmentation guidelines on high-resolution MRI designed to assess remaining volumes of the hippocampus and the parahippocampal cortices after medial temporal lobe (MTL) surgery could provide a useful tool to investigate the involvement of these anatomical regions in surgical outcomes and in human memory. For this purpose, we implemented an MRI volumetric analysis, already applied to healthy population or epileptic patient before surgery, to quantify the volume of the hippocampus, the temporopolar cortex and the regions of the parahippocampal gyrus (perirhinal, entorhinal and parahippocampal cortices) spared after unilateral MTL resection carried out to treat medically uncontrolled temporal lobe epilepsy (TLE). Based on the locations of remaining anatomical landmarks, we quantified the volume of these regions in 24 patients after MTL resection and in 16 control participants. Our results show that (1) mean volumes of these regions contralateral to the epileptic focus were similar to those of normal subjects, (2) volumetric measures obtained from the resected side were much smaller than those from the non-resected side or from normal values and (3) the extent of MTL resection was comparable in right or left MTL surgery. Individual analysis of patients showed that the parahippocampal cortex, as opposed to the other regions, was not systematically removed across patients. As a post-operative MRI-based method, it therefore proves valuable to assess group data as well as to explore differences between individual patients.

Adult↗

Changes in glial glutamate transporters in human epileptogenic hippocampus: inadequate explanation for high extracellular glutamate during seizures.

Temporal lobe epilepsy (TLE) with hippocampal sclerosis is associated with high extracellular glutamate levels, which could trigger seizures. Down-regulation of glial glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2) in sclerotic hippocampi may account for such increases. Their distribution was compared immunohistochemically in non-sclerotic and sclerotic hippocampi and localized only in astrocytes, with weaker immunoreactivity for both transporters in areas associated with pronounced neuronal loss, especially in CA1, but no decrease or even an increase in areas with less neuronal loss, like CA2 and the subiculum in the sclerotic group. Such compensatory changes in immunoreactivity may account for the lack of differences between the groups in immunoblot studies as blots show the average concentrations in the samples. These data suggest that differences in glial glutamate transporter distribution between the two groups of hippocampi may be an insufficient explanation for the high levels of extracellular glutamate in sclerotic seizure foci observed through in vivo dialysis studies.

Adolescent↗

Beneficial effects of FK506 for experimental temporal lobe epilepsy.

FK506, originally classified as an immunosuppressant, may also be implicated in some events in the central nervous system. FK506 elicits both neuroprotective and neurotrophic effects in vitro. FK506 is neuroprotective for focal cerebral ischemia, but it is not clear whether FK506 has neuroprotective effects for other brain diseases. In this study, we investigated possible neuroprotective effects of FK506 in experimental temporal lobe epilepsy (TLE) induced by kainic acid (KA) or trimethyltin (TMT). In rat models, we observed marked protection against seizures, abnormal behaviors, and accompanying delayed neuronal damage in the hippocampus by the systemic injection of FK506.

Aggression↗

Resting functional MRI with temporal clustering analysis for localization of epileptic activity without EEG.

We report on the methods and initial findings of a novel noninvasive technique, resting functional magnetic resonance imaging (fMRI) with temporal clustering analysis (TCA), for localizing interictal epileptic activity. Nine subjects were studied including six temporal lobe epilepsy (TLE) patients with confirmed localization indicated by successful seizure control after resection. The remaining three subjects had standard presurgical evaluations with inconsistent results or suspected extratemporal lobe foci. Peaks of activity, presumably epileptic, were detected in all nine subjects, using the resting functional MRI with temporal clustering analysis. In all six patients who underwent resective surgery, the fMRI with temporal clustering analysis accurately determined the epileptogenic hippocampal hemisphere (P = 0.005). In the three subjects without confirmed localization, the technique determined regions of activity consistent with those determined by the presurgical assessments. Though more studies are required to validate this technique, the results demonstrate the potential of the resting fMRI with temporal clustering technique to detect and localize epileptic activity without the need for simultaneous electroencephalography (EEG). The greatest potential benefit of this technique will be in the evaluation of patients with suspected extratemporal lobe epilepsy and patients whose standard assessments are discordant.

Adolescent↗

Spatial intralobar correlation of spike and slow wave activity localisations in focal epilepsies: a MEG analysis.

12 patients with focal epilepsy were examined by magnetoencephalography (MEG). Source localisations of interictal epileptiform activity (spikes) yielded clear results. Slow wave dipole density in the frequency range from 2 to 6 Hz, using time selections from an automatic principal component analysis (PCA), was calculated. Results of spike and slow wave dipole density localisations were superimposed on MR-images of each patient. Slow wave dipole densities were increased close to spike localisations. Distances between spike center of mass and slow wave maxima were calculated, average mean distance was 2.0 cm. Independant of the localisation in either TLE or ETLE a concordance of slow wave and spike localisations were found. Slow wave localisations were found in patients with lesions in MRI and patients with no abnormalities on the MRI. In comparison to healthy subjects, slow wave dipole density in patients with epilepsy was clearly increased. The localisation of slow wave dipole density yielded additional important information and may contribute to defining the irritative zone.

Adolescent↗

GABA(B1a), GABA(B1b) AND GABA(B2) mRNA variants expression in hippocampus resected from patients with temporal lobe epilepsy.

The aim of this study was to investigate the mRNA expression of the two GABA(B1) receptor isoforms and the GABA(B2) subunit, in human postmortem control hippocampal sections and in sections resected from epilepsy patients using quantitative in situ hybridisation autoradiography. Utilising human control hippocampal sections it was shown that the oligonucleotides employed were specific to the receptor. Hippocampal slices from surgical specimens obtained from patients with hippocampal sclerosis and temporal lobe epilepsy were compared with neurologically normal postmortem control subjects for neuropathology and GABA(B) mRNA expression. Neuronal loss was observed in most of the hippocampal subregions, but in the subiculum no significant difference was detected. The localisation of GABA(B1a) and GABA(B1b) isoform mRNAs in human control hippocampal sections supported and extended earlier studies using the GABA(B1) pan probe, which does not distinguish between the two GABA(B1) isoforms. Moreover, the GABA(B2) mRNA location confirmed the heterodimerisation of the receptor. Thus, although there was an apparent correlation between GABA(B1b) and GABA(B2), GABA(B1a) exhibited no such relationship. GABA(B1b) and GABA(B2) showed a similar intensity of expression whilst GABA(B1a) displayed a lower hybridisation signal. Comparison of the expression of the three mRNAs between control and epileptic subjects showed significant decreases or increases in different hippocampal subregions.GABA(B) isoforms and subunit mRNA expression per remaining neuron was significantly increased in the hilus and dentate gyrus. These results demonstrate that altered GABA(B) receptor mRNA expression occurs in human TLE; possibly the observed changes may also serve to counteract ongoing hyperexcitability.

Adult↗

Postoperative interictal spikes during sleep contralateral to the operated side is associated with unfavourable surgical outcome in patients with preoperative bitemporal spikes.

PURPOSE: To correlate the persistence of contralateral spikes during sleep after unilateral surgery with seizure outcome in a temporal lobe epilepsy (TLE) population and to test the existing hypotheses about the origin of the contralateral spikes in temporal lobe epilepsy. METHODS: In the 19 patients selected for this study unilateral temporal lobe surgery was performed. To investigate the course of bilateral interictal epileptiform discharges observed before surgery in awake or sleep over the temporal lobe contralateral to surgery, 24 h mobile 12 channel EEG recording was performed at minimum two, in average 4.6 (2-10) years after the surgery. RESULTS: The association of postoperative contralateral spikes and non-seizure free outcome was highly significant. The existence of unilateral pathology before surgery was highly predictive for good outcome and disappearance of contralateral spikes. The association between good seizure outcome, disappearance of contralateral spikes and the existence of unilateral pathology before surgery was also significant. Our data partially satisfies the expectations of both the "seizure induced" and mirror type secondary epileptogenesis hypotheses concerning origin of contralateral spikes, but were not completely congruent with either of them. CONCLUSIONS: Unfavourable surgical outcome in a temporal lobe epilepsy group with preoperative independent bilateral interictal spikes was associated with the persistence of postoperative contralateral spikes and lack of unilateral pathology. Compared with seizure outcome the presence/absence and distribution of postoperative interictal spikes in NREM sleep not entirely fit to the predictions of existing secondary epileptogenesis hypotheses.

Adolescent↗

Model based prognosis of postoperative object naming in left temporal lobe epilepsy.

Epilepsy surgery in the left temporal lobe is associated with a high risk of naming decline. In the present study, in 45 patients with left temporal lobe epilepsy (TLE) and confirmed left hemisphere language dominance, 13 (29%) patients demonstrated postoperative decrement >or=5 naming failures in the Boston Naming Test (BNT). Multivariate discriminant analysis with age at onset of epilepsy, age at first risk, age at operation and preoperative naming performance as predictors indicated that 12 (92%) patients with later naming decline could be identified preoperatively. Univariate group comparisons revealed that specifically patients with seizure onset later than 14 years without preceding risk factors (e.g., febrile seizures) are in danger of postoperative dysnomia. It is hypothesized, that there is a strong connection between stable naming performance and deviant intrahemispheric speech representation as a result of early brain damage and/or chronic seizures.

Adult↗

Neuropsychological tests with lateralizing value in patients with temporal lobe epilepsy: reconsidering material-specific theory.

PURPOSE: To assess the ability of neuropsychological tests to determine the side of seizure onset for preoperative assessment in patients with drug-resistant temporal lobe epilepsy. METHODS: Twenty-nine consecutive patients diagnosed with temporal lobe epilepsy (TLE), in whom the epileptogenic focus was clearly identified and localized to either the right or left hemisphere. Patients underwent a full neuropsychological assessment as part of their pre-surgical investigation, including the Boston Naming Test (BNT) and a variety of Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) and Wechsler Memory Scale-Third Edition (WMS-III) subtests. Two multivariate analyses of variance were carried out to assess differences on memory and language measures between groups according to side of epileptogenic focus. Binary logistic regression analysis was performed to find the sets of tests that best predicted the side of seizure onset (determined by EEG and MRI). RESULTS: Memory multivariate analysis of variance failed to show significant differences between the right- and left-sided groups. Among language measures, only the BNT revealed significant differences between the groups. The neuropsychological measures that best predicted the side of seizure onset were the BNT and Visual Reproduction II. CONCLUSIONS: Language measures predict the side of seizure focus better than memory measures. The results of this study in a sample of drug-resistant temporal lobe epilepsy patients challenge the memory material-specific theory for the side of seizure focus.

Adult↗

Does socio-economic advantage lead to a longer, healthier old age?

The effect of socio-economic disadvantage on mortality is well documented and differences exist even at older ages. However, whether this translates into differences in the quality of life lived at older ages is less well studied, and in particular in the proportion of remaining life spent without ill health (healthy life expectancy), a key UK Government target. Although there have been studies exploring socio-economic differences in disability-free life expectancy (DFLE) worldwide, these have tended to focus on a single measure of socio-economic advantage, for example, education, race, social class or income, with the majority based on cross-sectional data from younger populations. In this prospective study we examine differences in DFLE and total life expectancy (TLE) at older ages using a range of measures of socio-economic advantage. We use a longitudinal study of 1480 participants aged 75 years or over in 1988 registered with a UK primary care practice, who were followed up until 2003 with measurements at up to seven time points. Disability was defined as difficulty with any one of five activities of daily living. The largest differences in DFLE for both men and women were found for housing tenure. Women aged 75 years living in owned or mortgaged property could expect to live 1 year extra without disability compared with those living in rented accommodation, while for men the difference was almost 1.5 years. The effect of socio-economic advantage on disability-free and total life expectancies appeared to be larger for men than women. In women, socio-economic advantage had more effect on DFLE than total life expectancy for all indicators considered, thus the socio-economically advantaged experienced a compression of disability.

Aged↗