Gilles Naeije

An intrinsic mechanism of corticogenesis from embryonic stem cells

The cerebral cortex develops through the coordinated generation of dozens of neuronal subtypes, but the mechanisms involved remain unclear. Here we show that mouse embryonic stem cells, cultured without any morphogen but in the presence of a sonic hedgehog inhibitor, recapitulate in vitro the major milestones of cortical development, leading to the sequential generation of a diverse repertoire of neurons that display most salient features of genuine cortical pyramidal neurons. When grafted into the cerebral cortex, these neurons develop patterns of axonal projections corresponding to a wide range of cortical layers, but also to highly specific cortical areas, in particular visual and limbic areas, thereby demonstrating that the identity of a cortical area can be specified without any influence from the brain. The discovery of intrinsic corticogenesis sheds new light on the mechanisms of neuronal specification, and opens new avenues for the modelling and treatment of brain diseases.

Generation of cortical neurons from mouse embryonic stem cells

Embryonic stem cells (ESCs) constitute a tool of great potential in neurobiology, enabling the directed differentiation of specific neural cell types. We have shown recently that neurons of the cerebral cortex can be generated from mouse ESCs cultured in a chemically defined medium that contains no morphogen, but in the presence of the sonic hedgehog inhibitor cyclopamine. Corticogenesis from ESCs recapitulates the most important steps of cortical development, leading to the generation of multipotent cortical progenitors that sequentially produce cortical pyramidal neurons displaying distinct layer-specific identities. The protocol provides a most reductionist cellular model to tackle the complex mechanisms of cortical development and function, thereby opening new perspectives for the modeling of cortical diseases and the design of novel neurological treatments, while offering an alternative to animal use. In this protocol, we describe a method by which millions of cortical neurons can be generated in 2–3 weeks, starting from a single frozen vial of ESCs.

EEG patterns compatible with nonconvulsive status epilepticus are common in elderly patients with delirium: a prospective study with continuous EEG monitoring

INTRODUCTION Delirium is a leading cause of hospitalization and morbidity in elderly persons. Nonconvulsive status epilepticus (NCSE) and delirium share many risk factors. We tested the hypothesis that NCSE plays an important role in delirium by performing continuous EEG (cEEG) monitoring in elderly patients with delirium of any cause. MATERIAL AND METHODS Patients over 65 years old presenting with delirium in the emergency room were prospectively included and underwent either routine 20-minute EEG or cEEG within 24h after admission. Clinical, biological, and imaging characteristics, length of hospitalization, and outcome were compared between patients with possible NCSE and patients without epileptic discharges. RESULTS There were 32 patients in each group. Continuous EEG detected patterns compatible with NCSE in 28% and focal interictal epileptiform discharges (IEDs) in 16% of the patients. Routine EEG detected patterns compatible with NCSE in 6% and focal IEDs in 16% of the patients. History of cognitive impairment and use of antibiotics and hypernatremia were significantly associated with the presence of possible NCSE. Delirium in patients with possible NCSE was initially attributed to another cause in over 80% of the cases. Patterns compatible with NCSE were associated with a longer hospitalization stay and a higher mortality rate. CONCLUSION Electroencephalographic patterns compatible with NCSE are found in 28% of elderly with delirium when cEEG monitoring is performed. No clinical or paraclinical parameter can reliably distinguish elderly patients with delirium with or without patterns compatible with NCSE in the absence of cEEG monitoring. Elderly patients with delirium and patterns compatible with NCSE have significantly higher mortality rates and longer hospital stays.

Acute confusional state of unknown cause in the elderly: a study with continuous EEG monitoring.

INTRODUCTION Acute confusional state (ACS) is a frequent cause of emergency consultation in the elderly. Many causes of ACS are also risk factors for seizures. Both non-convulsive seizures and status epilepticus can cause acute confusion. The yield of routine EEG may not be optimal in case of prolonged post-ictal confusion. We thus, sought to evaluate the yield of CEEG in identifying seizures in elderly patients with ACS of unknown origin. METHODS We reviewed our CEEG database for patients over 75 years with ACS and collected EEG, CEEG and clinical information. RESULTS Thirty-one percent (15/48) of the CEEG performed in elderly patients were done for ACS. Routine EEG did not reveal any epileptic anomalies in 7/15 patients. Among those, CEEG identified interictal epileptiform discharges (IED) in 2 and NCSE in 1. In 8/15 patients, routine EEG revealed epileptiform abnormalities: 3 with IED (including 1 with periodic lateralized discharges), 3 with non-convulsive seizures (NCSz) and 2 with non-convulsive status epilepticus (NCSE). Among patients with only IED, CEEG revealed NCSz in 1 and NCSE in 2. CONCLUSION This retrospective study suggests that NCSz and NCSE may account for more cases of ACS than what was previously thought. A single negative routine EEG does not exclude this diagnosis. Continuous EEG (CEEG) monitoring is more revealing than routine EEG for the detection of NCSE and NCSz in confused elderly. The presence of IED in the first routine EEG strongly suggests concomitant NCSz or NCSE. Prospective studies are required to further determine the role of CEEG monitoring in the assessment of ACS in the elderly and to establish the incidence of NCSz and NCSE in this setting.

Acute behavioural change in a young woman evolving towards cerebellar syndrome.

Symptomatic paraneoplastic neurological syndromes are rare manifestations of cancers. Recently, a new type of encephalitis associated with antibodies against NMDA-glutamate receptors (A-NMDAR) was defined. The patients, usually young women, present with acute onset of psychiatric symptoms and decreased consciousness. We describe the case of a patient who presented with acute onset of delirium alternating with sub-comatose state. Blood analyses were within normal range. Lumbar puncture showed lymphocytic pleiocytosis. Brain gadolinium injected MRI, brain and full body PET scans were normal. Investigations led to suspect a paraneoplastic syndrome and a right ovarian teratoma and A-NMDAR were found and the teratoma removed. The remaining sequellae included a cerebellar syndrome seldom described before. As cerebellar and cortical neurons share the same excitatory pathway through NMDA-glutamate receptors, the cerebellar function impairment observed in our patient could be explained by a disabling action on glutamate NMDAR by the A-NMDAR.

Epileptic activities are common in older people with delirium

Delirium is responsible for up to 56% of hospital admissions in the elderly. Epilepsy and delirium share most risk factors and are both associated with confusion. The aim of this work was to study whether a link between epileptic activity (EA) and delirium existed, and if this link was relevant.

Multilevel Cortical Processing of Somatosensory Novelty: A Magnetoencephalography Study.

Using magnetoencephalography (MEG), this study investigates the spatio-temporal dynamics of the multilevel cortical processing of somatosensory change detection. Neuromagnetic signals of 16 healthy adult subjects (7 females and 9 males, mean age 29 ± 3 years) were recorded using whole-scalp-covering MEG while they underwent an oddball paradigm based on simple standard (right index fingertip tactile stimulation) and deviant (simultaneous right index fingertip and middle phalanx tactile stimulation) stimuli gathered into sequences to create and then deviate from stimulus patterns at multiple (local vs. global) levels of complexity. Five healthy adult subjects (3 females and 2 males, mean age 31, 6 ± 2 years) also underwent a similar oddball paradigm in which standard and deviant stimuli were flipped. Local deviations led to a somatosensory mismatch response peaking at 55–130 ms post-stimulus onset with a cortical generator located at the contralateral secondary somatosensory (cSII) cortex. The mismatch response was independent of the deviant stimuli physical characteristics. Global deviants led to a P300 response with cortical sources located bilaterally at temporo-parietal junction (TPJ) and supplementary motor area (SMA). The posterior parietal cortex (PPC) and the SMA were found to generate a contingent magnetic variation (CMV) attributed to top-down expectations. Amplitude of mismatch responses were modulated by top-down expectations and correlated with both the magnitude of the CMV and the P300 amplitude at the right TPJ. These results provide novel empirical evidence for a unified sensory novelty detection system in the human brain by linking detection of salient sensory stimuli in personal and extra-personal spaces to a common framework of multilevel cortical processing.

Transient CNS Deficits and Migrainous Auras in Individuals Without a History of Headache

To demonstrate that benign transient focal neurological symptoms represent equivalents of migraine auras without headache.

Neural Basis of Early Somatosensory Change Detection: A Magnetoencephalography Study.

The mismatch negativity (MMN) reflects the early detection of changes in sensory stimuli at the cortical level. The mechanisms underlying its genesis remain debated. This magnetoencephalography study investigates the spatio-temporal dynamics and the neural mechanisms of the magnetic somatosensory MMN. Somatosensory evoked magnetic fields elicited by tactile stimulation of the right fingertip (Single), tactile stimulation of the right middle phalanx and fingertip (Double) or omissions (Omitted) of tactile stimuli were studied in different paradigms: in oddballs where Double/Omitted followed a sequence of four Single, in sequences of two stimuli where Double occurred after one Single, and in random presentation of Double only. The predictability of Double occurrence in oddballs was also manipulated. Cortical sources of evoked responses were identified using equivalent current dipole modeling. Evoked responses elicited by Double were significantly different from those elicited by Single at the contralateral secondary somatosensory (cSII) cortex. Double elicited higher cSII cortex responses than Single when preceded by a sequence of four Single, compared to when they were preceded by one Single. Double elicited higher cSII cortex response when presented alone compared to when Double were preceded by one or a sequence of Single. Omitted elicited similar cSII cortex response than Single. Double in oddballs led to higher cSII cortex responses when less predictable. These data suggest that early tactile change detection involves mainly cSII cortex. The predictive coding framework probably accounts for the SII cortex response features observed in the different tactile paradigms.

Transient Neurologic Deficits: Can Transient Ischemic Attacks Be Discrimated from Migraine Aura without Headache?

BACKGROUND Transient neurologic deficits (TNDs) are often considered first to be transient ischemic attacks (TIAs) but TND with normal brain imaging is also characteristic of other prevalent conditions like migraine aura leading to potential confusion. We aimed to determine if migraine aura with headache (MA) and migraine aura without headache (MAWH) can be distinguished from TIA on clinical or paraclinical ground using validated international criteria. METHODS Clinical and paraclinical data from 32 patients with TIA were compared with 32 patients with MAWH and 32 with MA. Participants underwent a thorough evaluation including standardized clinical examination, laboratory testing, magnetic resonance imaging of the brain, cardiovascular work-up, and electroencephalogram. RESULTS Patient with TIA were significantly older (65.41 ± 16.93 years) than patients with MAWH (50.41 ± 19.69, P = .002) or MA (40.56 ± 11.72, P = .00001), and were mostly male (male:female = .82) compared with the 2 other groups. History of stroke, high blood pressure, and dyslipidemia were significantly more frequent in patients with TIA. Visual deficits occurred in 63% of patients with MAWH, 41% for patients with MA, and 10% for patients with TIA. In patients with TIA, the TND was inaugural in 94% of cases, conversely to MAWH and MA in which TND was inaugural in only 19% and 38%, respectively (P ≤ .0001). CONCLUSIONS Despite some sociodemographic, clinical, and paraclinical differences in the presentation of these TND, there is no feature accurately distinguishing between TIA and TND associated with migrainous phenomena when validated actual criteria are used, leading to probable confusion in most studies. There is a need to develop reliable criteria and/or tests for this purpose.