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
- dospělí MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mladý dospělý MeSH
- modafinil * farmakologie aplikace a dávkování MeSH
- mozeček * účinky léků diagnostické zobrazování metabolismus MeSH
- neokortex účinky léků metabolismus diagnostické zobrazování MeSH
- nervové dráhy účinky léků metabolismus MeSH
- stimulancia farmakologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie 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
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- malformace mozkové kůry * diagnostické zobrazování klasifikace patologie MeSH
- mozková kůra anatomie a histologie diagnostické zobrazování růst a vývoj MeSH
- neokortex anatomie a histologie MeSH
- polymikrogyrie diagnostické zobrazování klasifikace patologie MeSH
- šedá hmota * abnormality anatomie a histologie růst a vývoj MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy 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.
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
- biologická evoluce MeSH
- kognice fyziologie MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- neokortex metabolismus fyziologie MeSH
- neurogeneze fyziologie MeSH
- neurony metabolismus fyziologie MeSH
- paměť fyziologie MeSH
- proliferace buněk fyziologie MeSH
- proteiny aktivující GTPasu metabolismus MeSH
- úzkost metabolismus patofyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
- elektroencefalografie metody MeSH
- hipokampus fyziologie MeSH
- konsolidace paměti fyziologie MeSH
- lidé MeSH
- neokortex fyziologie MeSH
- spánek pomalých vln fyziologie MeSH
- spánek fyziologie MeSH
- thalamus fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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
- analýza jednotlivých buněk MeSH
- buňky klasifikace MeSH
- lidé MeSH
- neokortex cytologie MeSH
- neuroglie klasifikace MeSH
- neurony klasifikace MeSH
- terminologie jako téma MeSH
- transkriptom * MeSH
- výpočetní biologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy 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
- benzylaminy MeSH
- dospělí MeSH
- fenethylaminy MeSH
- halucinogeny aplikace a dávkování farmakologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mladý dospělý MeSH
- neokortex diagnostické zobrazování účinky léků metabolismus MeSH
- neuropsychologické testy MeSH
- osobnost účinky léků MeSH
- osobnostní testy MeSH
- pozitronová emisní tomografie MeSH
- psilocybin aplikace a dávkování farmakologie MeSH
- receptor serotoninový 5-HT2A účinky léků metabolismus MeSH
- všímavost * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
- adenosin fyziologie MeSH
- antikonvulziva aplikace a dávkování MeSH
- dinukleosidfosfáty aplikace a dávkování MeSH
- draslíkové kanály fyziologie MeSH
- hamartin genetika MeSH
- lidé MeSH
- membránové potenciály účinky léků MeSH
- myši transgenní MeSH
- myši MeSH
- neokortex účinky léků patofyziologie MeSH
- neurony účinky léků fyziologie MeSH
- receptor adenosinový A1 fyziologie MeSH
- signální transdukce účinky léků MeSH
- záchvaty patofyziologie prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
- buněčná diferenciace genetika MeSH
- chlorid-hydrogenuhličitanové antiportéry MeSH
- down regulace genetika MeSH
- embryo savčí MeSH
- hipokampus cytologie embryologie MeSH
- mutace genetika MeSH
- myši transgenní MeSH
- myši MeSH
- neokortex cytologie embryologie MeSH
- nervové kmenové buňky fyziologie MeSH
- neurogeneze fyziologie MeSH
- neuroglie MeSH
- neurony fyziologie MeSH
- počet buněk MeSH
- proliferace buněk genetika MeSH
- protein 2 podobný transkripčnímu faktoru 7 genetika metabolismus MeSH
- proteiny T-boxu metabolismus MeSH
- proteiny Wnt metabolismus MeSH
- retinální gangliové buňky fyziologie MeSH
- signální transdukce genetika MeSH
- transkripční faktory SOXB1 metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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
- dítě MeSH
- dospělí MeSH
- elektroencefalografie MeSH
- epilepsie temporálního laloku diagnostické zobrazování chirurgie MeSH
- fluorodeoxyglukosa F18 MeSH
- kojenec MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozek diagnostické zobrazování MeSH
- neokortex diagnostické zobrazování MeSH
- neurochirurgické výkony MeSH
- pozitronová emisní tomografie MeSH
- předškolní dítě MeSH
- radiofarmaka MeSH
- retrospektivní studie MeSH
- spánkový lalok diagnostické zobrazování MeSH
- věk při počátku nemoci MeSH
- výsledek terapie MeSH
- záchvaty diagnostické zobrazování patofyziologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
