Level of work performance was generally associated with severity of anxiety. Of the instruments tested, the WLQ and the WPAI questionnaire demonstrated acceptable validity and internal reliability.

Intraneuronal accumulation of hyperphosphorylated protein tau in paired helical filaments together with amyloid-␤ peptide (A␤) deposits confirm the clinical diagnosis of Alzheimer disease. A common cellular mechanism leading to the production of these potent toxins remains elusive. Here we show that, in cultured neurons, membrane depolarization induced a calcium-mediated transient phosphorylation of both microtubule-associated protein tau and amyloid precursor protein (APP), followed by a dephosphorylation of these proteins. Phosphorylation was mediated by glycogen synthase kinase 3 and cyclin-dependent kinase 5 protein kinases, while calcineurin was responsible for dephosphorylation. Following the transient phosphorylation of APP, intraneuronal A␤ accumulated and induced neurotoxicity. Phosphorylation of APP on Thr-668 was indispensable for intraneuronal accumulation of A␤. Our data demonstrate that an increase in cytosolic calcium concentration induces modifications of neuronal metabolism of APP and tau, similar to those found in Alzheimer disease.The coexistence of neurofibrillary tangles and senile plaques in the brain confirms the clinical diagnosis of Alzheimer disease (AD) 2 (1). Intraneuronal neurofibrillary tangles are made of paired helical filaments containing the hyperphosphorylated microtubule-associated protein tau (2). The amyloid core of extracellular senile plaques contains fibrils of amyloid ␤ peptide (A␤) (3, 4), which results from the cleavage of the amyloid precursor protein APP (5). The most compelling evidence that A␤ is the causative agent of AD comes from observations on genetic mutations that cause familial forms of AD. Mutations of APP or presenilin genes alter the processing of APP (6), giving rise to increased production of A␤, in particular of A␤ containing 42 amino acids (A␤1-42), which is more prone to aggregation (7). These genetic data founded the amyloid cascade hypothesis (8) that implies that plaques should develop before tangles. However, neuropathological studies have indicated that the initial development of tangles precedes the development of amyloid plaques by at least two decades (9). To reconcile these controversial observations, it has been proposed that the initial neurofibrillary changes are independent of A␤ (10), while this process is accelerated by the presence of A␤, which can stimulate AD-like phosphorylation of tau in neuronal cultures (11). For many years, the amyloid cascade hypothesis maintained that memory failure in AD derived from neuronal death induced by insoluble extracellular deposits of amyloid fibrils. Newer findings, however, demonstrate that accumulation of intraneuronal A␤ is neurotoxic (12, 13). A common alteration of the neuronal metabolism of APP and tau, leading to the production of both hyperphosphorylated tau and A␤, remains elusive. Here we show that in cultured neurons membrane depolarization induced a calcium-mediated transient phosphorylation of APP and tau by the Cdk5 and GSK3 protein kinases, followed by a dephosphorylation of both p...

The insula, particularly its posterior portion, is often regarded as a primary cortex for pain. However, this interpretation is largely based on reverse inference, and a specific involvement of the insula in pain has never been demonstrated. Taking advantage of the high spatiotemporal resolution of direct intracerebral recordings, we investigated whether the human insula exhibits local field potentials (LFPs) specific for pain. Forty-seven insular sites were investigated. Participants received brief stimuli belonging to four different modalities (nociceptive, vibrotactile, auditory, and visual). Both nociceptive stimuli and non-nociceptive vibrotactile, auditory, and visual stimuli elicited consistent LFPs in the posterior and anterior insula, with matching spatial distributions. Furthermore, a blind source separation procedure showed that nociceptive LFPs are largely explained by multimodal neural activity also contributing to non-nociceptive LFPs. By revealing that LFPs elicited by nociceptive stimuli reflect activity unrelated to nociception and pain, our results confute the widespread assumption that these brain responses are a signature for pain perception and its modulation.

Objective Although most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology. Methods We retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video‐EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic–ischemic encephalopathy. Results Twenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p < .001). Sodium channel‐blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy. Significance Seizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by sodium channel‐blocking antiseizure medications.