Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs.

The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 min after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, SRS frequencies and durations, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d.), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d.), diazepam (4 mg/kg, b.i.d.), and phenobarbital (25 and 50 mg/kg, b.i.d.). Valproate, diazepam, and phenobarbital significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. These data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) and partially sensitive to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). Accordingly, this model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy.

Thalamus and focal to bilateral seizures: A multiscale cognitive imaging study.

OBJECTIVE: To investigate the functional correlates of recurrent secondarily generalized seizures in temporal lobe epilepsy (TLE) using task-based fMRI as a framework to test for epilepsy-specific network rearrangements. Because the thalamus modulates propagation of temporal lobe onset seizures and promotes cortical synchronization during cognition, we hypothesized that occurrence of secondarily generalized seizures, i.e., focal to bilateral tonic-clonic seizures (FBTCS), would relate to thalamic dysfunction, altered connectivity, and whole-brain network centrality. METHODS: FBTCS occur in a third of patients with TLE and are a major determinant of disease severity. In this cross-sectional study, we analyzed 113 patients with drug-resistant TLE (55 left/58 right), who performed a verbal fluency fMRI task that elicited robust thalamic activation. Thirty-three patients (29%) had experienced at least one FBTCS in the year preceding the investigation. We compared patients with TLE-FBTCS to those without FBTCS via a multiscale approach, entailing analysis of statistical parametric mapping (SPM) 12-derived measures of activation, task-modulated thalamic functional connectivity (psychophysiologic interaction), and graph-theoretical metrics of centrality. RESULTS: Individuals with TLE-FBTCS had less task-related activation of bilateral thalamus, with left-sided emphasis, and left hippocampus than those without FBTCS. In TLE-FBTCS, we also found greater task-related thalamotemporal and thalamomotor connectivity, and higher thalamic degree and betweenness centrality. Receiver operating characteristic curves, based on a combined thalamic functional marker, accurately discriminated individuals with and without FBTCS. CONCLUSIONS: In TLE-FBTCS, impaired task-related thalamic recruitment coexists with enhanced thalamotemporal connectivity and whole-brain thalamic network embedding. Altered thalamic functional profiles are proposed as imaging biomarkers of active secondary generalization.

Machado de Assis' Original Sin.

Machado de Assis (1839-1908) suffered from temporal lobe epilepsy, probably with origin in the non-dominant hemisphere. The evidence for this is provided by the detailed reports of the characteristics of his seizures by his contemporaries and by his correspondence with other writers. He was treated with bromides and homeopathy. It is unclear whether his neurological disorder influenced his artistic performance. What is evident is that he was deeply ashamed of the disease - he avoided the word "epilepsy" and just wrote about it in his personal correspondence with friends in the last years of his life. Though controversial, he had no clear traces of personality disorders linked to his temporal lobe epilepsy. Despite all his adversities, including being "mulatto," having a stutter, being of humble origins, and epileptic in a period when there was no efficacious therapy and a profound stigma associated with the disease, Machado de Assis became one of the most important Brazilian writers of all times.

Radiosurgery versus open surgery for mesial temporal lobe epilepsy: The randomized, controlled ROSE trial.

OBJECTIVE: To compare stereotactic radiosurgery (SRS) versus anterior temporal lobectomy (ATL) for patients with pharmacoresistant unilateral mesial temporal lobe epilepsy (MTLE). METHODS: This randomized, single-blinded, controlled trial recruited adults eligible for open surgery among 14 centers in the USA, UK, and India. Treatment was either SRS at 24 Gy to the 50% isodose targeting mesial structures, or standardized ATL. Outcomes were seizure remission (absence of disabling seizures between 25 and 36 months), verbal memory (VM), and quality of life (QOL) at 36-month follow-up. RESULTS: A total of 58 patients (31 in SRS, 27 in ATL) were treated. Sixteen (52%) SRS and 21 (78%) ATL patients achieved seizure remission (difference between ATL and SRS = 26%, upper 1-sided 95% confidence interval = 46%, P value at the 15% noninferiority margin = .82). Mean VM changes from baseline for 21 English-speaking, dominant-hemisphere patients did not differ between groups; consistent worsening occurred in 36% of SRS and 57% of ATL patients. QOL improved with seizure remission. Adverse events were anticipated cerebral edema and related symptoms for some SRS patients, and cerebritis, subdural hematoma, and others for ATL patients. SIGNIFICANCE: These data suggest that ATL has an advantage over SRS in terms of proportion of seizure remission, and both SRS and ATL appear to have effectiveness and reasonable safety as treatments for MTLE. SRS is an alternative to ATL for patients with contraindications for or with reluctance to undergo open surgery.

Memory Rehabilitation Strategies in Nonsurgical Temporal Lobe Epilepsy: A Review.

People with temporal lobe epilepsy (TLE) who have not undergone epilepsy surgery often complain of memory deficits. Cognitive rehabilitation is employed as a remedial intervention in clinical settings, but research is limited and findings concerning efficacy and the criteria for choosing different approaches have been inconsistent. We aimed to appraise existing evidence on memory rehabilitation in nonsurgical individuals with temporal lobe epilepsy and to ascertain the effectiveness of specific strategies. A scoping review was preferred given the heterogeneous nature of the interventions. A comprehensive literature search using MEDLINE, EMBASE, CINAHL, AMED, Scholars Portal/PSYCHinfo, Proceedings First, and ProQuest Dissertations and Theses identified articles published in English before February 2016. The search retrieved 372 abstracts. Of 25 eligible studies, six were included in the final review. None included pediatric populations. Strategies included cognitive training, external memory aids, brain training, and noninvasive brain stimulation. Selection criteria tended to be general. Overall, there was insufficient evidence to make definitive conclusions regarding the efficacy of traditional memory rehabilitation strategies, brain training, and noninvasive brain stimulation. The review suggests that cognitive rehabilitation in nonsurgical TLE is underresearched and that there is a need for a systematic evaluation in this population.

Ginkgo biloba L. attenuates spontaneous recurrent seizures and associated neurological conditions in lithium-pilocarpine rat model of temporal lobe epilepsy through inhibition of mammalian target of rapamycin pathway hyperactivation.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. (Ginkgoaceae) has been widely used in traditional medicine for variety of neurological conditions particularly behavioral and memory impairments. AIM OF THE STUDY: The present study was envisaged to explore the effect of a standardized fraction of Ginkgo biloba leaves (GBbf) in rat model of lithium-pilocarpine induced spontaneous recurrent seizures, and associated behavioral impairments and cognitive deficit. MATERIALS AND METHODS: Rats showing appearance of spontaneous recurrent seizures following lithium pilocarpine (LiPc)-induced status epilepticus (SE) were treated with different doses of GBbf or vehicle for subsequent 4 weeks. The severity of seizures and aggression in rats were scored following treatment with GBbf. Further, open field, forced swim, novel object recognition and Morris water maze tests were conducted. Histopathological, protein levels and gene expression studies were performed in the isolated brains. RESULTS: Treatment with GBbf reduced seizure severity score and aggression in epileptic animals. Improved spatial cognitive functions and recognition memory, along with reduction in anxiety-like behavior were also observed in the treated animals. Histopathological examination by Nissl staining showed reduction in neuronal damage in the hippocampal pyramidal layer. The dentate gyrus and Cornu Ammonis 3 regions of the hippocampus showed reduction in mossy fiber sprouting. GBbf treatment attenuated ribosomal S6 and pS6 proteins, and hippocampal mTOR, Rps6 and Rps6kb1 mRNA levels. CONCLUSIONS: The results of present study concluded that GBbf treatment suppressed lithium-pilocarpine induced spontaneous recurrent seizures severity and incidence with improved cognitive functions, reduced anxiety-like behavior and aggression. The effect was found to be due to inhibition of mTOR pathway hyperactivation linked with recurrent seizures.

Interictal epileptic discharge correlates with global and frontal cognitive dysfunction in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) with hippocampal sclerosis has widespread effects on structural and functional connectivity and often entails cognitive dysfunction. EEG is mandatory to disentangle interactions in epileptic and physiological networks which underlie these cognitive comorbidities. Here, we examined how interictal epileptic discharges (IEDs) affect cognitive performance. METHODS: Thirty-four patients (right TLE=17, left TLE=17) were examined with 24-hour video-EEG and a battery of neuropsychological tests to measure intelligence quotient and separate frontal and temporal lobe functions. Hippocampal segmentation of high-resolution T1-weighted imaging was performed with FreeSurfer. Partial correlations were used to compare the number and distribution of clinical interictal spikes and sharp waves with data from imagery and psychological tests. RESULTS: The number of IEDs was negatively correlated with executive functions, including verbal fluency and intelligence quotient (IQ). Interictal epileptic discharge affected cognitive function in patients with left and right TLE differentially, with verbal fluency strongly related to temporofrontal spiking. In contrast, IEDs had no clear effects on memory functions after corrections with partial correlations for age, age at disease onset, disease duration, and hippocampal volume. CONCLUSION: In patients with TLE of long duration, IED occurrence was strongly related to cognitive deficits, most pronounced for frontal lobe function. These data suggest that IEDs reflect dysfunctional brain circuitry and may serve as an independent biomarker for cognitive comorbidity.

Adhesio interthalamica and cavum septum pellucidum in mesial temporal lobe epilepsy.

The absence of the adhesio interthalamica (AI; also called interthalamic adhesion or massa intermedia) and the presence of a large cavum septum pellucidum (CSP) later in life have been related to neurodevelopmental alterations and have not been systematically investigated in epilepsy to date. This study carried out a MRI evaluation of the AI and CSP in a large sample with mesial temporal lobe epilepsy (MTLE). A total of 179 patients, classified according to the side of the epileptogenic focus, and 156 age- and sex-balanced healthy controls were assessed. Between-group comparisons of the prevalence and length of both AI and CSP were conducted. Neuropsychological assessments were also performed in 160 MTLE patients. The patients exhibited reduction in the AI prevalence (P < 0.05; FDR-uncorrected) and length (P < 0.05; FDR-corrected) when compared to controls. Patients without AI showed lower scores in a proportion of neuropsychological tests than patients with AI. No CSP differences were found between MTLE patients and controls. These results support that AI anomalies have clinical significance in MTLE, as well as indicate that neurodevelopmental alterations may be implicated in this disorder.

Characterization and prediction of the recognition of emotional faces and emotional bursts in temporal lobe epilepsy.

INTRODUCTION: The present study sought to characterize and predict the recognition of emotional stimuli (presented in a visual or auditory modality) by patients with temporal lobe epilepsy (TLE). METHOD: Fifty TLE patients and 50 matched controls performed two emotion recognition tasks (emotional faces and emotional bursts). Neutral stimuli were also presented, and emotional biases were monitored by analyzing errors. Demographic, cognitive, psychobehavioral and (in TLE patients only) clinical and quality of life data were also recorded. RESULTS: Compared with controls, TLE patients were impaired in the recognition of fear expressions in both visual and auditory modality tasks. However, impairments in the two channels were not always concomitant on the individual level. In the visual modality, recognition of disgust and neutral expressions was significantly worse in TLE patients. In the auditory modality, nonsignificant trends toward poor recognition of disgust and neutral expressions were observed. Negative biases were noted in TLE patients; expressions of fear (faces and bursts) were more frequently misinterpreted as disgust, and neutral facial expressions were more frequently misinterpreted as sadness. Impairments in the recognition of facial fear were less pronounced in left TLE patients who (according to structural magnetic resonance imaging, MRI) did not have any brain lesions. In TLE patients, low levels of social support (a quality of life parameter) were associated with worse recognition of facial disgust, and higher levels of apathy were associated with better recognition of neutral faces. CONCLUSIONS: TLE patients are impaired in some aspects of emotion recognition with both visual and auditory stimuli, although the differential impact of TLE on these modalities requires further research. These emotional impairments are related to quality of life and psychobehavioral parameters.

Hippocampal-thalamic wiring in medial temporal lobe epilepsy: Enhanced connectivity per hippocampal voxel.

OBJECTIVE: Medial temporal lobe epilepsy (TLE) with hippocampal sclerosis is often accompanied by widespread changes in ipsilateral and contralateral white matter connectivity. Recent studies have proposed that patients may show pathologically enhanced wiring of the limbic circuits. To better address this issue, we specifically probed connection patterns between hippocampus and thalamus and examined their impact on cognitive function. METHODS: A group of 44 patients with TLE (22 with right and 22 with left hippocampal sclerosis) and 24 healthy control participants were examined with high-resolution T1 imaging, memory functional magnetic resonance imaging (fMRI) and probabilistic diffusion tractography. Thirty-four patients had further extensive neuropsychological testing. After whole brain segmentation with FreeSurfer, tractography streamline samples were drawn with hippocampus as the seed and thalamus as the target region. Two tractography strategies were applied: The first targeted the anatomic thalamic volume segmented in FreeSurfer and the second a functional region of interest in the mediodorsal thalamus derived from the activation during delayed recognition memory. RESULTS: We found a pronounced enhancement of connectivity between the sclerotic hippocampus and the ipsilateral thalamus both in the right and left TLE as compared to healthy control participants. This finding held for both the anatomically and the functionally defined thalamic target. Although differences were apparent in the number of absolute fibers, they were most pronounced when correcting for hippocampal volume. In terms of cognitive function, the number of hippocampal-thalamic connections was negatively correlated with performance in a variety of executive tasks, notably in the Trail Making Test, thus suggesting that the pathologic wiring did not compensate cognitive curtailing. SIGNIFICANCE: We suggest that TLE is accompanied by an abnormal and dysfunctional enhancement of connectivity between the hippocampus and the thalamus, which is maximal on the side of the sclerosis. This pathologic pattern of limbic wiring might reflect structural remodeling along common pathways of seizure propagation.

Temporal lobe epilepsy: decreased thalamic resting-state functional connectivity and their relationships with alertness performance.

OBJECTIVES: Studies have provided evidence regarding the pathology of the thalamus in patients with temporal lobe epilepsy (TLE). The thalamus, particularly the right thalamus, is one of the subcortical structures that are most uniformly accepted as being significantly involved in alertness. Moreover, alertness impairment in epilepsy has been reported. This study aimed to investigate alterations in thalamic resting-state functional connectivity (FC) and their relationships with alertness performance in patients with TLE; an issue that has not yet been addressed. METHODS: A total of 15 patients with right TLE (rTLE) and 16 healthy controls were recruited for the present study. All of the participants underwent a resting-state functional magnetic resonance imaging (fMRI) scan and the attention network test (ANT). Whole-brain voxel-wise FC analyses were applied to extract the thalamic resting-state functional networks in the patients with rTLE and healthy controls, and the differences between the two groups were evaluated. Correlation analyses were employed to examine the relationships between alterations in thalamic FC and alertness performance in patients with rTLE. RESULTS: Compared to the healthy controls, the FC within and between the bilateral thalamus was decreased in the patients with rTLE. Moreover, in the patient group, the bilateral anterior cingulate cortex (ACC) and subcortical regions, including the bilateral brainstem, cerebellum, putamen, right caudate nucleus, and amygdala, exhibited decreased FC with the ipsilateral thalamus (p<0.05, AlphaSim corrected, cluster size>44) but not with the contralateral thalamus (p<0.05, AlphaSim corrected, cluster size>43). The intrinsic and phasic alertness performances of the patients were impaired (p=0.001 and p<0.001, respectively) but not correlated with decreased thalamic FC. Meanwhile, the alertness performance was not altered in right TLE but was negatively correlated with decreased thalamic FC with ACC (p<0.05). CONCLUSIONS: Our findings highlight the functional importance of the thalamus in TLE pathology and suggest that damage to the thalamic resting-state functional networks, particularly ipsilateral to the epileptogenic focus, is present in patients with TLE.

Cognitive rehabilitation in epilepsy: An evidence-based review.

AIM OF THE STUDY: To review the modalities of cognitive rehabilitation (CR), outcome endpoints, and the levels of evidence of efficacy of different interventions. METHODS: A systematic research in Pubmed, Psychinfo, and SCOPUS was performed assessing the articles written in the entire period covered by these databases till December 2013. Articles in English, Spanish or French were evaluated. A manual research evaluated the references of all of the articles. The experimental studies were classified according to the level of evidence of efficacy, using a standardized Italian method (SPREAD, 2007), adopting the criteria reported by Cicerone et al. (2000, 2011). RESULTS: Eighteen papers were classified into two reviews, four papers dealing with the principles and efficacy of CR in epilepsy, a methodological paper, a single-case report, a multiple-case report, and nine experimental papers. Most studies involved patients with temporal lobe epilepsy. Different types of CR were used to treat patients with epilepsy. A holistic rehabilitation approach was more useful than selective interventions to treat memory and attention disturbances. CONCLUSIONS: CR may be a useful tool to treat cognitive impairment in patients with epilepsy. However, the modalities of treatment and outcome endpoints are important concerns of clinical care and research. Controlled studies are needed to determine the efficacy of rehabilitation in well-defined groups of patients with epilepsy.

Exaltation in temporal lobe epilepsy: neuropsychiatric symptom or portal to the divine?

Religiosity is a prominent feature of the Geschwind syndrome, a behavioural pattern found in some cases of temporal lobe epilepsy. Since the 1950s, when Wilder Penfield induced spiritual feelings by experimental manipulation of the temporal lobes, development of brain imaging technology has revealed neural correlates of intense emotional states, spurring the growth of neurotheology. In their secular empiricism, psychiatry, neurology and psychology are inclined to pathologise deviant religious expression, thereby reinforcing the dualism of objective and phenomenal worlds. Considering theological perspectives and the idea of cosmic consciousness, the authors urge a holistic approach to the spiritual events of epileptic aura, potentially leading to a deeper understanding of the mind and its transcendent potential.

Psychiatric comorbidities in temporal lobe epilepsy: possible relationships between psychotic disorders and involvement of limbic circuits / Comorbidades psiquiátricas na epilepsia do lobo temporal: possíveis relações entre desordens psicóticas e comprometimento de circuitos límbicos

OBJECTIVE: Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. METHODS: In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. CONCLUSIONS: TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.

OBJETIVO: Existem cada vez mais evidências de que o sistema límbico está envolvido na patologia das comorbidades psiquiátricas em pacientes com epilepsia do lobo temporal (ELT). Nosso objetivo foi elaborar um desenho conceitual descrevendo como aspectos neuropatológicos e de conectividade podem contribuir para o desenvolvimento de psicose em pacientes com ELT. MÉTODOS: Nesta revisão, achados clínicos e neuropatológicos, e especialmente os aspectos da circuitaria límbica, foram examinados em conjunto para auxiliar nossa compreensão sobre a associação entre ELT e psicose. Achados em modelos animais de epilepsia e esquizofrenia também foram levados em consideração. CONCLUSÕES: ELT e comorbidades psiquiátricas coexistem com maior frequência que o predito pela associação ao acaso. Dano e desregulação entre estruturas anatômicas críticas, como hipocampo, amígdala, tálamo, e córtices temporal, frontal e cingulado podem predispor o cérebro com ELT à psicose. Estudos sobre efeitos comportamentais e eletrofisiológicos do abrasamento elétrico e injeções de substâncias neuroativas em modelos animais podem oferecer pistas sobre como crises límbicas em humanos aumentam a vulnerabilidade de pacientes com ELT a sintomas psiquiátricos.

Psychiatric comorbidities in temporal lobe epilepsy: possible relationships between psychotic disorders and involvement of limbic circuits.

OBJECTIVE: Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. METHODS: In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. CONCLUSIONS: TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.

Seizure precipitants and inhibiting factors in mesial temporal lobe epilepsy.

Epileptic seizures may be triggered by both nonspecific facilitating factors and specific reflex epileptic mechanisms. These consist of sensory or cognitive inputs activating neural networks that, due to some functional instability, may respond with an epileptic discharge. The aim of this study was to determine the prevalence and nature of self-perceived seizure-inducing and -inhibiting factors in patients with mesial temporal lobe epilepsy (MTLE) followed from March 3rd to December 8th, 2009 at the Centro de Epilepsia de Santa Catarina Outpatient Clinic of the Hospital Governador Celso Ramos in Florianópolis, Brazil and their relation to demographics, epilepsy-related variables and anxiety level. Of the 71 patients, 60 (84.5%) patients identified at least one seizure trigger, and 36 (50.7%) patients identified inhibiting factors. In order of frequency, the most freely recalled precipitants were nervousness (58.8%), worrying (21.6%) and menstruation (19.6%), while the precipitants that were most frequently identified from a list were worrying (73.2%), anxiety (66.2%) and anger (53.5%). Knowledge of precipitant factors may have implications on the treatment and seizure control of patients.

Impaired extinction of fear and maintained amygdala-hippocampal theta synchrony in a mouse model of temporal lobe epilepsy.

PURPOSE: The relationship between epilepsy and fear has received much attention. However, seizure-modulated fear and physiologic or structural correlates have not been examined systematically, and the underlying basics of network levels remain unclear to date. Therefore, this project was set up to characterize the neurophysiologic basis of seizure-related fear and the contribution of the amygdala-hippocampus system. METHODS: The experimental strategy was composed of the following steps: (1) use of the mouse pilocarpine model of temporal lobe epilepsy (TLE); (2) behavioral analyses of anxiety states in the elevated plus maze test, light-dark avoidance test, and Pavlovian fear conditioning; and (3) probing neurophysiologic activity patterns in amygdala-hippocampal circuits in freely behaving mice. RESULTS: Our results displayed no significant differences in basic anxiety levels comparing mice that developed spontaneous recurrent seizures (SRS) and controls. Furthermore, conditioned fear memory retrieval was not influenced in SRS mice. However, during fear memory extinction, SRS mice showed an extended freezing behavior and a maintained amygdala-hippocampal theta frequency synchronization compared to controls. DISCUSSION: These results indicate specific alterations in conditioned fear behavior and related neurophysiologic activities in the amygdala-hippocampal network contributing to impaired fear memory extinction in mice with TLE. Clinically, the nonextinguished fear memories may well contribute to the experience of fear in patients with TLE.

Temporal lobectomy: resection volume, neuropsychological effects, and seizure outcome.

OBJECTIVE: The goal of the work described here was to evaluate relationships among resection volume, seizure outcome, and cognitive morbidity after temporal lobectomy for intractable epilepsy. METHODS: Thirty patients with mesial temporal sclerosis were evaluated pre- and postoperatively with the Wechsler Adult Intelligence Scale III, Wechsler Memory Scale III, and three-dimensional coronal spoiled gradient recall acquisition MRI. Preoperative whole-brain volumes were calculated with Statistical Parametric Mapping. Resection volume was calculated by manual tracing. Systat was used for statistical analysis. RESULTS: All resections included the temporal tip, at least 1cm of the superior temporal gyrus, and 3 to 5cm of the middle and inferior temporal gyri. Left were significantly smaller than right temporal resections. Seizure-free patients had significantly larger resections. Immediate verbal memory was significantly worse after left temporal lobectomy. Surgical outcome and resection volume did not affect postoperative neuropsychological results. CONCLUSIONS: Dominant temporal lobe resections are associated with immediate verbal memory deficits. Larger resection volume was associated with improved seizure control but not worse cognitive outcome.

Limbic event-related potentials to words and pictures in the presurgical evaluation of temporal lobe epilepsy.

We recorded limbic event-related potentials (ERPs) with intrahippocampal depth electrodes in a more demanding verbal and an easier pictorial continuous recognition task in patients undergoing presurgical evaluations of their medical refractory mesial temporal lobe epilepsies (MTLE). In all cases depth electrodes were implanted because non-invasive studies could not demonstrate unilateral seizure-onset unequivocally. For the present study we only considered 24 patients who eventually were found to suffer from unilateral MTLE, in whom hippocampal sclerosis (HS) was confirmed histologically, and who were seizure-free post-operatively. We found that the rhinal anterior medial temporal lobe N400 (AMTL-N400) to first presentations of words but not to pictures was reduced in amplitude on the side of seizure origin. Our data suggest that limbic ERPs to words are more sensitive to the epileptogenic process than those to pictures. Thus, if limbic ERPs are recorded as part of invasive presurgical evaluations, verbal instead of pictorial recognition paradigms should be employed.