Antonio Gil-Nagel

A fast pathway for fear in human amygdala

A fast, subcortical pathway to the amygdala is thought to have evolved to enable rapid detection of threat. This pathways existence is fundamental for understanding nonconscious emotional responses, but has been challenged as a result of a lack of evidence for short-latency fear-related responses in primate amygdala, including humans. We recorded human intracranial electrophysiological data and found fast amygdala responses, beginning 74-ms post-stimulus onset, to fearful, but not neutral or happy, facial expressions. These responses had considerably shorter latency than fear responses that we observed in visual cortex. Notably, fast amygdala responses were limited to low spatial frequency components of fearful faces, as predicted by magnocellular inputs to amygdala. Furthermore, fast amygdala responses were not evoked by photographs of arousing scenes, which is indicative of selective early reactivity to socially relevant visual information conveyed by fearful faces. These data therefore support the existence of a phylogenetically old subcortical pathway providing fast, but coarse, threat-related signals to human amygdala.

Adverse effects of antiepileptic drugs.

Adverse effects of antiepileptic drugs (AEDs) are considered by patients to be at least as important as repetitive seizures in terms of quality of life. AED toxicity is frequent and contributes to a high proportion of treatment failures. Despite its high prevalence and clinical relevance, screening for adverse reactions to AEDs is not systematically included in everyday clinical practice; therefore it is very likely that it remains underestimated. Because there is little difference among AEDs in terms of efficacy, drug selection is often based on the adverse effects profile. AED toxicity is classified according to different parameters, such as severity, time of occurrence, organ system involvement, and mechanisms of action. Although most toxic reactions to drugs can be predicted from cumulative experience, prevention is not always possible, since multiple mechanisms and individual susceptibility to each drug participate in the final outcome. However, adverse effects can be reduced and appropriate action can be taken in time by means of a high degree of suspicion, knowledge of risk factors, and close follow-up. This article highlights factors to consider for detecting and managing AED adverse effects.

Remote Effects of Hippocampal Sclerosis on Effective Connectivity during Working Memory Encoding: A Case of Connectional Diaschisis?

Accumulating evidence suggests a role for the medial temporal lobe (MTL) in working memory (WM). However, little is known concerning its functional interactions with other cortical regions in the distributed neural network subserving WM. To reveal these, we availed of subjects with MTL damage and characterized changes in effective connectivity while subjects engaged in WM task. Specifically, we compared dynamic causal models, extracted from magnetoencephalographic recordings during verbal WM encoding, in temporal lobe epilepsy patients (with left hippocampal sclerosis) and controls. Bayesian model comparison indicated that the best model (across subjects) evidenced bilateral, forward, and backward connections, coupling inferior temporal cortex (ITC), inferior frontal cortex (IFC), and MTL. MTL damage weakened backward connections from left MTL to left ITC, a decrease accompanied by strengthening of (bidirectional) connections between IFC and MTL in the contralesional hemisphere. These findings provide novel evidence concerning functional interactions between nodes of this fundamental cognitive network and sheds light on how these interactions are modified as a result of focal damage to MTL. The findings highlight that a reduced (top-down) influence of the MTL on ipsilateral language regions is accompanied by enhanced reciprocal coupling in the undamaged hemisphere providing a first demonstration of “connectional diaschisis.”

Network reconfiguration and working memory impairment in mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) is the most prevalent form of focal epilepsy, and hippocampal sclerosis (HS) is considered the most frequent associated pathological finding. Recent connectivity studies have shown that abnormalities, either structural or functional, are not confined to the affected hippocampus, but can be found in other connected structures within the same hemisphere, or even in the contralesional hemisphere. Despite the role of hippocampus in memory functions, most of these studies have explored network properties at resting state, and in some cases compared connectivity values with neuropsychological memory scores. Here, we measured magnetoencephalographic responses during verbal working memory (WM) encoding in left mTLE patients and controls, and compared their effective connectivity within a frontotemporal network using dynamic causal modelling. Bayesian model comparison indicated that the best model included bilateral, forward and backward connections, linking inferior temporal cortex (ITC), inferior frontal cortex (IFC), and the medial temporal lobe (MTL). Test for differences in effective connectivity revealed that patients exhibited decreased ipsilesional MTL-ITC backward connectivity, and increased bidirectional IFC-MTL connectivity in the contralesional hemisphere. Critically, a negative correlation was observed between these changes in patients, with decreases in ipsilesional coupling among temporal sources associated with increases contralesional frontotemporal interactions. Furthermore, contralesional frontotemporal interactions were inversely related to task performance and level of education. The results demonstrate that unilateral sclerosis induced local and remote changes in the dynamic organization of a distributed network supporting verbal WM. Crucially, pre-(peri) morbid factors (educational level) were reflected in both cognitive performance and (putative) compensatory changes in physiological coupling.

Anterobasal Temporal Lobe Lesions Alter Recurrent Functional Connectivity within the Ventral Pathway during Naming

An increasing amount of evidence supports a crucial role for the anterior temporal lobe (ATL) in semantic processing. Critically, a selective disruption of the functional connectivity between left and right ATLs in patients with chronic aphasic stroke has been illustrated. The aim of the current study was to evaluate the consequences that lesions on the ATL have on the neurocognitive network supporting semantic cognition. Unlike previous work, in this magnetoencephalography study we selected a group of patients with small lesions centered on the left anteroventral temporal lobe before surgery. We then used an effective connectivity method (i.e., dynamic causal modeling) to investigate the consequences that these lesions have on the functional interactions within the network. This approach allowed us to evaluate the directionality of the causal interactions among brain regions and their associated connectivity strengths. Behaviorally, we found that semantic processing was altered when patients were compared with a strictly matched group of controls. Dynamic causal modeling for event related responses revealed that picture naming was associated with a bilateral frontotemporal network, encompassing feedforward and feedback connections. Comparison of specific network parameters between groups revealed that patients displayed selective network adjustments. Specifically, backward connectivity from anterior to posterior temporal lobe was decreased in the ipsilesional hemisphere, whereas it was enhanced in the contralesional hemisphere. These results reinforce the relevance of ATL in semantic memory, as well as its amodal organization, and highlight the role of feedback connections in enabling the integration of the semantic information.

A clinical and magnetoencephalography study of MRI-negative startle epilepsy

OBJECTIVEnThe goal of this study was to investigate clinical findings, ictal semiology, and results of video/electroencephalography (video/EEG), and magnetoencephalography (MEG) in patients with startle epilepsy and normal brain MRI.nnnMETHODSnFour patients (mean age 12.5 years) with startle epilepsy were investigated with MRI, video/EEG, and MEG.nnnRESULTSnEpilepsy diagnosis was established in childhood, and all had spontaneous and reflex seizures. Reflex seizures were triggered by sudden, unexpected sounds and tactile stimuli. The neurological examinations and MRIs were normal. MEG recordings showed focal epileptiform activity. An ictal MEG was obtained in one patient. Source modeling yielded dipole sources in right central frontal region.nnnCONCLUSIONnThe present study demonstrates that the origin of epileptiform activity in startle epilepsy can be localized in brain areas associated with supplementary motor seizures, even in patients with normal brain MRI. MEG adds complementary information to the localization of epileptiform activity and can be useful in planning invasive studies in cases evaluated for epilepsy surgery.

Modulation of medial temporal lobe activity in epilepsy patients with hippocampal sclerosis during verbal working memory.

It has been traditionally assumed that medial temporal lobe (MTL) is not required for working memory (WM). However, animal lesion and electrophysiological studies and human neuropsychological and neuroimaging studies have provided increasing evidences of a critical involvement of MTL in WM. Based on previous findings, the central aim of this study was to investigate the contribution of the MTL to verbal WM encoding. Here, we used magnetoencephalography (MEG) to compare the patterns of MTL activation of 9 epilepsy patients suffering from left hippocampal sclerosis with those of 10 healthy matched controls while they performed a verbal WM task. MEG recordings allow detailed tracking of the time course of MTL activation. We observed impaired WM performance associated with changes in the dynamics of MTL activity in epilepsy patients. Specifically, whereas patients showed decreased activity in damaged MTL, activity in the contralateral MTL was enhanced, an effect that became significant in the 600- to 700-ms interval after stimulus presentation. These findings strongly support the crucial contribution of MTL to verbal WM encoding and provide compelling evidence for the proposal that MTL contributes to both episodic memory and WM. Whether this pattern is signaling reorganization or a normal use of a damaged structure is discussed.

Biomagnetic profiles of verbal memory success in patients with mesial temporal lobe epilepsy

The risk of cognitive decline after mesial temporal lobe (MTL) resection in the dominant hemisphere for treatment of epilepsy has been assessed with the intracarotid amytal procedure and functional neuroimaging. In this study we used magnetoencephalography (MEG) to analyze memory profiles in patients with left hippocampal sclerosis (HS). Biomagnetic brain activity related to successful memory was compared in nine patients with left HS and nine age-matched controls. Patients manifested a higher number of activity sources over the right inferior parietal lobe in the late portion of the time window, and higher activity in the right than in the left MTL between 400 and 800 ms. This was reinforced by a -0.46 MTL laterality index, which indicates right MTL dominance. Controls showed a higher number of dipoles in the left anterior ventral prefrontal region, between 400 and 600 ms, and in the left MTL across the whole time window. Three patients who underwent a left temporal lobectomy, were seizure free, and who did not exhibit memory impairment after left temporal lobectomy, showed no activity in the left MTL presurgically. These results could support the ability of MEG to describe the time-modulated brain activity related to memory success in patients with epilepsy with left HS.

Specificity of electroclinical features in the diagnosis of ring chromosome 20

BACKGROUNDnRing chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drug-resistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20.nnnMETHODSnIn this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug-resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases.nnnRESULTSnWe identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%. Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad.nnnCONCLUSIONSnIn our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted.

Validez de las escalas clínicas y de contenido del Inventario Multifásico de Personalidad de Minnesota-2 para el diagnóstico de crisis no epilépticas psicógenas

INTRODUCTIONnThe use of the Multiphasic Personality Inventory Minnesota 2 (MMPI-2) for the diagnosis of psychogenic non-epileptic seizures (PNES) is controversial. This study examines the validity of the clinical scales and, unlike previous works, the content scales.nnnMETHODSnCross-sectional study of 209 patients treated in the epilepsy unit. We performed a logistic regression analysis, taking video-electroencephalography as the reference test, and as predictor variables age, sex, IQ and clinical (model A) or content scales (model B) of the MMPI-2. The models were selected according to the Aikake index and compared using the DeLong test.nnnRESULTSnWe analyzed 37 patients with PNES alone, or combined with seizures, and 172 patients with seizures only. The model consisting of sex, Hs (hypochondriasis) and Pa (paranoia) showed a sensitivity of 77.1%, a specificity of 76.8%, a percentage of correct classification of 76.8%, and an area under the curve (AUC) of 0.836 for diagnosing CNEP. Model B, consisting of sex, HEA (health concerns) and FRS (fears), showed a sensitivity of 65.7%, a specificity of 78.0%, a percentage of correct classification of 75.9% and an AUC of 0.840. DeLongs test did not detect significant differences.nnnCONCLUSIONSnThe MMPI-2 has a moderate validity for the diagnosis of PNES in patients referred to an epilepsy unit. Using content scales does not significantly improve results from the clinical scales.