BACKGROUND: Modafinil is primarily used to treat narcolepsy but is also used as an off-label cognitive enhancer. Functional magnetic resonance imaging studies indicate that modafinil modulates the connectivity of neocortical networks primarily involved in attention and executive functions. However, much less is known about the drug's effects on subcortical structures. Following preliminary findings, we evaluated modafinil's activity on the connectivity of distinct cerebellar regions with the neocortex. We assessed the spatial relationship of these effects with the expression of neurotransmitter receptors/transporters. METHODS: Patterns of resting-state functional magnetic resonance imaging connectivity were estimated in 50 participants from scans acquired pre- and postadministration of a single (100 mg) dose of modafinil (n = 25) or placebo (n = 25). Using specific cerebellar regions as seeds for voxelwise analyses, we examined modafinil's modulation of cerebellar-neocortical connectivity. Next, we conducted a quantitative evaluation of the spatial overlap between the modulation of cerebellar-neocortical connectivity and the expression of neurotransmitter receptors/transporters obtained by publicly available databases. RESULTS: Modafinil increased the connectivity of crus I and vermis IX with prefrontal regions. Crus I connectivity changes were associated with the expression of dopaminergic D2 receptors. The vermis I-II showed enhanced coupling with the dorsal anterior cingulate cortex and matched the expression of histaminergic H3 receptors. The vermis VII-VIII displayed increased connectivity with the visual cortex, an activity associated with dopaminergic and histaminergic neurotransmission. CONCLUSIONS: Our study reveals modafinil's modulatory effects on cerebellar-neocortical connectivity. The modulation mainly involves crus I and the vermis and spatially overlaps the distribution of dopaminergic and histaminergic receptors.

• MeSH
• Adult MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Young Adult MeSH
• Modafinil * pharmacology   administration & dosage   MeSH
• Cerebellum * drug effects   diagnostic imaging   metabolism   MeSH
• Neocortex drug effects   metabolism   diagnostic imaging   MeSH
• Neural Pathways drug effects   metabolism   MeSH
• Wakefulness-Promoting Agents pharmacology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

Vývoj kortexu se děje postupně pomocí migrace jednotlivých neuronálních populací tak, že se vytváří laminace nejprve nejhlubší vrstvy, poté postupně migrují neurony přes ni a tvoří u neokortexu postupně jeho šest vrstev. Migrační poruchy vývoje kortexu zahrnují fokální, laminární a subkortikální formu kortikální heterotopie, lyssencefalii a mezi poruchy migrace a vrstvení kortexu patří i polymikrogyrie. Přehledová práce podává přehled o morfologii kortexu a jednotlivých typech migračních poruch a obrazu v magnetické rezonanci.

Development of the neocortex is the action of the successive migration of the individual neuronal populations in pattern, that the deepest lamina is created at first, the others are developer one by one migrating through the previously formed, all six laminae are developed at the end of migration. Migration disorders are covered cortical heterotopias (nodular, laminar, subcortical), lissencephaly and also polymicrogyria. The article gives the review of the cortical morphology and individual migration disorders and their magnetic resonance imaging.

• MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Malformations of Cortical Development * diagnostic imaging   classification   pathology   MeSH
• Cerebral Cortex anatomy & histology   diagnostic imaging   growth & development   MeSH
• Neocortex anatomy & histology   MeSH
• Polymicrogyria diagnostic imaging   classification   pathology   MeSH
• Gray Matter * abnormalities   anatomy & histology   growth & development   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Stereology-based methods provide the current state-of-the-art approaches for accurate quantification of numbers and other morphometric parameters of biological objects in stained tissue sections. The advent of artificial intelligence (AI)-based deep learning (DL) offers the possibility of improving throughput by automating the collection of stereology data. We have recently shown that DL can effectively achieve comparable accuracy to manual stereology but with higher repeatability, improved throughput, and less variation due to human factors by quantifying the total number of immunostained cells at their maximal profile of focus in extended depth of field (EDF) images. In the first of two novel contributions in this work, we propose a semi-automatic approach using a handcrafted Adaptive Segmentation Algorithm (ASA) to automatically generate ground truth on EDF images for training our deep learning (DL) models to automatically count cells using unbiased stereology methods. This update increases the amount of training data, thereby improving the accuracy and efficiency of automatic cell counting methods, without a requirement for extra expert time. The second contribution of this work is a Multi-channel Input and Multi-channel Output (MIMO) method using a U-Net deep learning architecture for automatic cell counting in a stack of z-axis images (also known as disector stacks). This DL-based digital automation of the ordinary optical fractionator ensures accurate counts through spatial separation of stained cells in the z-plane, thereby avoiding false negatives from overlapping cells in EDF images without the shortcomings of 3D and recurrent DL models. The contribution overcomes the issue of under-counting errors with EDF images due to overlapping cells in the z-plane (masking). We demonstrate the practical applications of these advances with automatic disector-based estimates of the total number of NeuN-immunostained neurons in a mouse neocortex. In summary, this work provides the first demonstration of automatic estimation of a total cell number in tissue sections using a combination of deep learning and the disector-based optical fractionator method.

• MeSH
• Algorithms MeSH
• Humans MeSH
• Mice MeSH
• Neocortex * MeSH
• Neurons MeSH
• Cell Count methods   MeSH
• Artificial Intelligence * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Neocortex expansion during human evolution provides a basis for our enhanced cognitive abilities. Yet, which genes implicated in neocortex expansion are actually responsible for higher cognitive abilities is unknown. The expression of human-specific ARHGAP11B in embryonic/foetal mouse, ferret and marmoset neocortex was previously found to promote basal progenitor proliferation, upper-layer neuron generation and neocortex expansion during development, features commonly thought to contribute to increased cognitive abilities. However, a key question is whether this phenotype persists into adulthood and if so, whether cognitive abilities are indeed increased. Here, we generated a transgenic mouse line with physiological ARHGAP11B expression that exhibits increased neocortical size and upper-layer neuron numbers persisting into adulthood. Adult ARHGAP11B-transgenic mice showed altered neurobehaviour, notably increased memory flexibility and a reduced anxiety level. Our data are consistent with the notion that neocortex expansion by ARHGAP11B, a gene implicated in human evolution, underlies some of the altered neurobehavioural features observed in the transgenic mice, such as the increased memory flexibility, a neocortex-associated trait, with implications for the increase in cognitive abilities during human evolution.

• MeSH
• Biological Evolution MeSH
• Cognition physiology   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neocortex metabolism   physiology   MeSH
• Neurogenesis physiology   MeSH
• Neurons metabolism   physiology   MeSH
• Memory physiology   MeSH
• Cell Proliferation physiology   MeSH
• GTPase-Activating Proteins metabolism   MeSH
• Anxiety metabolism   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The dialogue between cortex and hippocampus is known to be crucial for sleep-dependent memory consolidation. During slow wave sleep, memory replay depends on slow oscillation (SO) and spindles in the (neo)cortex and sharp wave-ripples (SWRs) in the hippocampus. The mechanisms underlying interaction of these rhythms are poorly understood. We examined the interaction between cortical SO and hippocampal SWRs in a model of the hippocampo-cortico-thalamic network and compared the results with human intracranial recordings during sleep. We observed that ripple occurrence peaked following the onset of an Up-state of SO and that cortical input to hippocampus was crucial to maintain this relationship. A small fraction of ripples occurred during the Down-state and controlled initiation of the next Up-state. We observed that the effect of ripple depends on its precise timing, which supports the idea that ripples occurring at different phases of SO might serve different functions, particularly in the context of encoding the new and reactivation of the old memories during memory consolidation. The study revealed complex bidirectional interaction of SWRs and SO in which early hippocampal ripples influence transitions to Up-state, while cortical Up-states control occurrence of the later ripples, which in turn influence transition to Down-state.

• MeSH
• Electroencephalography methods   MeSH
• Hippocampus physiology   MeSH
• Memory Consolidation physiology   MeSH
• Humans MeSH
• Neocortex physiology   MeSH
• Sleep, Slow-Wave physiology   MeSH
• Sleep physiology   MeSH
• Thalamus physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body.

• MeSH
• Single-Cell Analysis MeSH
• Cells classification   MeSH
• Humans MeSH
• Neocortex cytology   MeSH
• Neuroglia classification   MeSH
• Neurons classification   MeSH
• Terminology as Topic MeSH
• Transcriptome * MeSH
• Computational Biology MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

A single dose of the serotonin 2A receptor (5-HT2AR) agonist psilocybin can have long-lasting beneficial effects on mood, personality, and potentially on mindfulness, but underlying mechanisms are unknown. Here, we for the first time conduct a study that assesses psilocybin effects on cerebral 5-HT2AR binding with [11C]Cimbi-36 positron emission tomography (PET) imaging and on personality and mindfulness. Ten healthy and psychedelic-naïve volunteers underwent PET neuroimaging of 5-HT2AR at baseline (BL) and one week (1W) after a single oral dose of psilocybin (0.2-0.3 mg/kg). Personality (NEO PI-R) and mindfulness (MAAS) questionnaires were completed at BL and at three-months follow-up (3M). Paired t-tests revealed statistically significant increases in personality Openness (puncorrected = 0.04, mean change [95%CI]: 4.2[0.4;∞]), which was hypothesized a priori to increase, and mindfulness (pFWER = 0.02, mean change [95%CI]: 0.5 [0.2;0.7]). Although 5-HT2AR binding at 1W versus BL was similar across individuals (puncorrected = 0.8, mean change [95%CI]: 0.007 [-0.04;0.06]), a post hoc linear regression analysis showed that change in mindfulness and 5-HT2AR correlated negatively (β [95%CI] = -5.0 [-9.0; -0.9], pFWER= 0.046). In conclusion, we confirm that psilocybin intake is associated with long-term increases in Openness and - as a novel finding - mindfulness, which may be a key element of psilocybin therapy. Cerebral 5-HT2AR binding did not change across individuals but the negative association between changes in 5-HT2AR binding and mindfulness suggests that individual change in 5-HT2AR levels after psilocybin is variable and represents a potential mechanism influencing long-term effects of psilocybin on mindfulness.

• MeSH
• Benzylamines MeSH
• Adult MeSH
• Phenethylamines MeSH
• Hallucinogens administration & dosage   pharmacology   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Young Adult MeSH
• Neocortex diagnostic imaging   drug effects   metabolism   MeSH
• Neuropsychological Tests MeSH
• Personality drug effects   MeSH
• Personality Tests MeSH
• Positron-Emission Tomography MeSH
• Psilocybin administration & dosage   pharmacology   MeSH
• Receptor, Serotonin, 5-HT2A drug effects   metabolism   MeSH
• Mindfulness * MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/-), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/- mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.

• MeSH
• Adenosine physiology   MeSH
• Anticonvulsants administration & dosage   MeSH
• Dinucleoside Phosphates administration & dosage   MeSH
• Potassium Channels physiology   MeSH
• Tuberous Sclerosis Complex 1 Protein genetics   MeSH
• Humans MeSH
• Membrane Potentials drug effects   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neocortex drug effects   physiopathology   MeSH
• Neurons drug effects   physiology   MeSH
• Receptor, Adenosine A1 physiology   MeSH
• Signal Transduction drug effects   MeSH
• Seizures physiopathology   prevention & control   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Generation of neurons in the embryonic neocortex is a balanced process of proliferation and differentiation of neuronal progenitor cells. Canonical Wnt signalling is crucial for expansion of radial glial cells in the ventricular zone and for differentiation of intermediate progenitors in the subventricular zone. We detected abundant expression of two transcrtiption factors mediating canonical Wnt signalling, Tcf7L1 and Tcf7L2, in the ventricular zone of the embryonic neocortex. Conditional knock-out analysis showed that Tcf7L2, but not Tcf7L1, is the principal Wnt mediator important for maintenance of progenitor cell identity in the ventricular zone. In the absence of Tcf7L2, the Wnt activity is reduced, ventricular zone markers Pax6 and Sox2 are downregulated and the neuroepithelial structure is severed due to the loss of apical adherens junctions. This results in decreased proliferation of radial glial cells, the reduced number of intermediate progenitors in the subventricular zone and hypoplastic forebrain. Our data show that canonical Wnt signalling, which is essential for determining the neuroepithelial character of the neocortical ventricular zone, is mediated by Tcf7L2.

• MeSH
• Cell Differentiation genetics   MeSH
• Chloride-Bicarbonate Antiporters MeSH
• Down-Regulation genetics   MeSH
• Embryo, Mammalian MeSH
• Hippocampus cytology   embryology   MeSH
• Mutation genetics   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neocortex cytology   embryology   MeSH
• Neural Stem Cells physiology   MeSH
• Neurogenesis physiology   MeSH
• Neuroglia MeSH
• Neurons physiology   MeSH
• Cell Count MeSH
• Cell Proliferation genetics   MeSH
• Transcription Factor 7-Like 2 Protein genetics   metabolism   MeSH
• T-Box Domain Proteins metabolism   MeSH
• Wnt Proteins metabolism   MeSH
• Retinal Ganglion Cells physiology   MeSH
• Signal Transduction genetics   MeSH
• SOXB1 Transcription Factors metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

OBJECTIVE: The aim of this study was to assess clinical and electrophysiological differences within a group of patients with magnetic-resonance-imaging-negative temporal lobe epilepsy (MRI-negative TLE) according to seizure onset zone (SOZ) localization in invasive EEG (IEEG). METHODS: According to SOZ localization in IEEG, 20 patients with MRI-negative TLE were divided into either having mesial SOZ-mesial MRI-negative TLE or neocortical SOZ-neocortical MRI-negative TLE. We evaluated for differences between these groups in demographic data, localization of interictal epileptiform discharges (IEDs), and the ictal onset pattern in semiinvasive EEG and in ictal semiology. RESULTS: Thirteen of the 20 patients (65%) had mesial MRI-negative TLE and 7 of the 20 patients (35%) had neocortical MRI-negative TLE. The differences between mesial MRI-negative TLE and neocortical MRI-negative TLE were identified in the distribution of IEDs and in the ictal onset pattern in semiinvasive EEG. The patients with neocortical MRI-negative TLE tended to have more IEDs localized outside the anterotemporal region (p=0.031) and more seizures without clear lateralization of ictal activity (p=0.044). No other differences regarding demographic data, seizure semiology, surgical outcome, or histopathological findings were found. CONCLUSIONS: According to the localization of the SOZ, MRI-negative TLE had two subgroups: mesial MRI-negative TLE and neocortical MRI-negative TLE. The groups could be partially distinguished by an analysis of their noninvasive data (distribution of IEDs and lateralization of ictal activity). This differentiation might have an impact on the surgical approach.

• MeSH
• Child MeSH
• Adult MeSH
• Electroencephalography MeSH
• Epilepsy, Temporal Lobe diagnostic imaging   surgery   MeSH
• Fluorodeoxyglucose F18 MeSH
• Infant MeSH
• Humans MeSH
• Magnetic Resonance Imaging methods   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Brain diagnostic imaging   MeSH
• Neocortex diagnostic imaging   MeSH
• Neurosurgical Procedures MeSH
• Positron-Emission Tomography MeSH
• Child, Preschool MeSH
• Radiopharmaceuticals MeSH
• Retrospective Studies MeSH
• Temporal Lobe diagnostic imaging   MeSH
• Age of Onset MeSH
• Treatment Outcome MeSH
• Seizures diagnostic imaging   physiopathology   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH