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1.
Brain Nerve ; 72(11): 1151-1157, 2020 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-33191294

RESUMO

Current inputs with a specific frequency tend to be output as a large voltage response in some neurons. This property is called resonance and is thought to be the basis for the frequency response of neurons. In this review, I summarize the molecules required for generating resonance.


Assuntos
Modelos Neurológicos , Neurônios , Humanos , Potenciais da Membrana
2.
Phys Rev Lett ; 125(12): 128102, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016724

RESUMO

Neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, show characteristic degradation of structural brain networks. This degradation eventually leads to changes in the network dynamics and degradation of cognitive functions. Here, we model the progression in terms of coupled physical processes: The accumulation of toxic proteins, given by a nonlinear reaction-diffusion transport process, yields an evolving brain connectome characterized by weighted edges on which a neuronal-mass model evolves. The progression of the brain functions can be tested by simulating the resting-state activity on the evolving brain network. We show that while the evolution of edge weights plays a minor role in the overall progression of the disease, dynamic biomarkers predict a transition over a period of 10 years associated with strong cognitive decline.


Assuntos
Demência/patologia , Modelos Neurológicos , Doenças Neurodegenerativas/patologia , Animais , Relógios Biológicos , Encéfalo/patologia , Encéfalo/fisiopatologia , Morte Celular/fisiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Conectoma/métodos , Demência/fisiopatologia , Humanos , Camundongos , Doenças Neurodegenerativas/fisiopatologia , Neurônios/patologia
3.
Nat Commun ; 11(1): 5046, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028816

RESUMO

Signal loss in blood oxygen level-dependent (BOLD) functional neuroimaging is common and can lead to misinterpretation of findings. Here, we reconstructed compromised fMRI signal using deep machine learning. We trained a model to learn principles governing BOLD activity in one dataset and reconstruct artificially compromised regions in an independent dataset, frame by frame. Intriguingly, BOLD time series extracted from reconstructed frames are correlated with the original time series, even though the frames do not independently carry any temporal information. Moreover, reconstructed functional connectivity maps exhibit good correspondence with the original connectivity maps, indicating that the model recovers functional relationships among brain regions. We replicated this result in two healthy datasets and in patients whose scans suffered signal loss due to intracortical electrodes. Critically, the reconstructions capture individual-specific information. Deep machine learning thus presents a unique opportunity to reconstruct compromised BOLD signal while capturing features of an individual's own functional brain organization.


Assuntos
Mapeamento Encefálico/métodos , Córtex Cerebral/diagnóstico por imagem , Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Adolescente , Adulto , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/fisiologia , Conjuntos de Dados como Assunto , Estimulação Encefálica Profunda , Feminino , Voluntários Saudáveis , Humanos , Masculino , Modelos Neurológicos , Oxigênio/sangue , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Adulto Jovem
4.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2938-2941, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018622

RESUMO

Electrical brain stimulation (EBS) has been actively researched because of its clinical application and usefulness in brain research. However, its effect on individual neurons remains uncertain, as each neuron's response to EBS is highly variable and dependent on its morphology and the axis in which a neuron lies. Hence, our goal was to investigate the way that neuronal morphology affects the cellular response to extracellular stimulation from multiple directions. In this computational study, we observed that the varying neuronal morphology and direction of applied electrical field (EF) had some influence on the excitation threshold, which generates an action potential. Further, change of the excitation threshold depending on EF directions was observed.Clinical Relevance- These findings would help us to understand the variability in the modulatory effects of EBS at the cellular level and would be the basis for understanding the packed fibers' responses to EBS. Ultimately, considering EBS' clinical application, it may also help to predict patient's results from EBS treatment.


Assuntos
Modelos Neurológicos , Neurônios , Encéfalo , Estimulação Elétrica , Eletricidade , Humanos
5.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3629-3633, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018788

RESUMO

Deep brain stimulation (DBS) has evolved to an important treatment for several drug-resistant neurological and psychiatric disorders, such as epilepsy, Parkinson's disease, essential tremor and dystonia. Despite general effectiveness of DBS, however, its mechanisms of action are not completely understood. Simulations are commonly used to predict the volume of tissue activated (VTA) around DBS electrodes, which in turn helps interpreting clinical outcomes and understand therapeutic mechanisms. Computational models are commonly used to visualize the extend of volume of activated tissue (VTA) for different stimulation schemes, which in turn helps interpreting and understanding the outcomes. The degree of model complexity, however, can affect the predicted VTA. In this work we investigate the effect of volume conductor model complexity on the predicted VTA, when the VTA is estimated from activation function field metrics. Our results can help clinicians to decide what level of model complexity is suitable for their specific need.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson , Biofísica , Simulação por Computador , Humanos , Modelos Neurológicos , Doença de Parkinson/terapia
6.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3634-3637, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018789

RESUMO

Deep brain stimulation (DBS) involves activation of targeted brain tissue through implantable electrodes to treat neurological disorders. In this study, two novel electrode designs, recessed flat-contact and recessed curvature-contact models were developed where the electrode contacts were recessed to a specified depth to improve directional selectivity. Furthermore, the contact geometry was also modified for the recessed curvature-contact model in order to obtain a hemispherical configuration that will help increase current steering and reduce the propensity of tissue damage. The predicted tissue damage produced by these models were compared to the standard array model using the Shannon tissue damage model criteria. Furthermore, the volume of tissue activated by each of the electrode models was analyzed, and the radial projection relative to the total projection of each geometry was determined as a measure of directional selectivity. Based on the trends observed in the current density, tissue damage, and volume of tissue activated (VTA) analyses, it is inferred that the recessed contact electrode geometries help improve directional selectivity and safety of DBS.


Assuntos
Estimulação Encefálica Profunda , Encéfalo , Eletrodos Implantados , Matemática , Modelos Neurológicos
7.
Nat Commun ; 11(1): 5440, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116148

RESUMO

Despite recent progress in understanding multisensory decision-making, a conclusive mechanistic account of how the brain translates the relevant evidence into a decision is lacking. Specifically, it remains unclear whether perceptual improvements during rapid multisensory decisions are best explained by sensory (i.e., 'Early') processing benefits or post-sensory (i.e., 'Late') changes in decision dynamics. Here, we employ a well-established visual object categorisation task in which early sensory and post-sensory decision evidence can be dissociated using multivariate pattern analysis of the electroencephalogram (EEG). We capitalize on these distinct neural components to identify when and how complementary auditory information influences the encoding of decision-relevant visual evidence in a multisensory context. We show that it is primarily the post-sensory, rather than the early sensory, EEG component amplitudes that are being amplified during rapid audiovisual decision-making. Using a neurally informed drift diffusion model we demonstrate that a multisensory behavioral improvement in accuracy arises from an enhanced quality of the relevant decision evidence, as captured by the post-sensory EEG component, consistent with the emergence of multisensory evidence in higher-order brain areas.


Assuntos
Percepção Auditiva/fisiologia , Tomada de Decisões/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica , Adolescente , Adulto , Comportamento de Escolha/fisiologia , Eletroencefalografia/estatística & dados numéricos , Feminino , Humanos , Masculino , Modelos Neurológicos , Modelos Psicológicos , Análise Multivariada , Estimulação Luminosa , Adulto Jovem
8.
PLoS One ; 15(10): e0238578, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33001981

RESUMO

The spiral ganglion neurons constitute the primary connection between auditory hair cells and the brain. The spiral ganglion afferent fibers and their synapse with hair cells do not regenerate to any significant degree in adult mammalian ears after damage. We have investigated gene expression changes after kainate-induced disruption of the synapses in a neonatal cochlear explant model in which peripheral fibers and the afferent synapse do regenerate. We compared gene expression early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration. These analyses revealed a total of 2.5% differentially regulated transcripts (588 out of 24,000) based on a threshold of p<0.005. Inflammatory response genes as well as genes involved in regeneration of neural circuits were upregulated in the spiral ganglion neurons and organ of Corti, where the hair cells reside. Prominent genes upregulated at several time points included genes with roles in neurogenesis (Elavl4 and Sox21), neural outgrowth (Ntrk3 and Ppp1r1c), axonal guidance (Rgmb and Sema7a), synaptogenesis (Nlgn2 and Psd2), and synaptic vesicular function (Syt8 and Syn1). Immunohistochemical and in situ hybridization analysis of genes that had not previously been described in the cochlea confirmed their cochlear expression. The time course of expression of these genes suggests that kainate treatment resulted in a two-phase response in spiral ganglion neurons: an acute response consistent with inflammation, followed by an upregulation of neural regeneration genes. Identification of the genes activated during regeneration of these fibers suggests candidates that could be targeted to enhance regeneration in adult ears.


Assuntos
Células Ciliadas Auditivas/fisiologia , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Neurônios Aferentes/fisiologia , Animais , Animais Recém-Nascidos , Expressão Gênica/efeitos dos fármacos , Células Ciliadas Auditivas/efeitos dos fármacos , Inflamação/genética , Inflamação/fisiopatologia , Ácido Caínico/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Neurogênese/genética , Neurogênese/fisiologia , Gânglio Espiral da Cóclea/citologia , Gânglio Espiral da Cóclea/fisiologia , Sinapses/fisiologia , Técnicas de Cultura de Tecidos
9.
Science ; 369(6510): 1432-1433, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32943513
10.
Nat Commun ; 11(1): 4491, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901033

RESUMO

The functionality of the nervous system requires transmission of information along axons with high speed and precision. Conductance velocity depends on axonal diameter whereas signaling precision requires a block of electrical crosstalk between axons, known as ephaptic coupling. Here, we use the peripheral nervous system of Drosophila larvae to determine how glia regulates axonal properties. We show that wrapping glial differentiation depends on gap junctions and FGF-signaling. Abnormal glial differentiation affects axonal diameter and conductance velocity and causes mild behavioral phenotypes that can be rescued by a sphingosine-rich diet. Ablation of wrapping glia does not further impair axonal diameter and conductance velocity but causes a prominent locomotion phenotype that cannot be rescued by sphingosine. Moreover, optogenetically evoked locomotor patterns do not depend on conductance speed but require the presence of wrapping glial processes. In conclusion, our data indicate that wrapping glia modulates both speed and precision of neuronal signaling.


Assuntos
Drosophila melanogaster/fisiologia , Animais , Animais Geneticamente Modificados , Axônios/fisiologia , Diferenciação Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Larva/citologia , Larva/fisiologia , Locomoção/fisiologia , Modelos Neurológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neuroglia/citologia , Neuroglia/fisiologia , Optogenética , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/fisiologia , Fenótipo , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Transdução de Sinais
11.
Nat Commun ; 11(1): 4518, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908146

RESUMO

The human brain is specialized for face processing, yet we sometimes perceive illusory faces in objects. It is unknown whether these natural errors of face detection originate from a rapid process based on visual features or from a slower, cognitive re-interpretation. Here we use a multifaceted approach to understand both the spatial distribution and temporal dynamics of illusory face representation in the brain by combining functional magnetic resonance imaging and magnetoencephalography neuroimaging data with model-based analysis. We find that the representation of illusory faces is confined to occipital-temporal face-selective visual cortex. The temporal dynamics reveal a striking evolution in how illusory faces are represented relative to human faces and matched objects. Illusory faces are initially represented more similarly to real faces than matched objects are, but within ~250 ms, the representation transforms, and they become equivalent to ordinary objects. This is consistent with the initial recruitment of a broadly-tuned face detection mechanism which privileges sensitivity over selectivity.


Assuntos
Reconhecimento Facial/fisiologia , Ilusões/fisiologia , Modelos Neurológicos , Lobo Temporal/fisiologia , Córtex Visual/fisiologia , Adolescente , Adulto , Mapeamento Encefálico , Simulação por Computador , Feminino , Humanos , Imagem por Ressonância Magnética , Magnetoencefalografia , Masculino , Neuroimagem , Estimulação Luminosa , Tempo de Reação , Lobo Temporal/diagnóstico por imagem , Córtex Visual/diagnóstico por imagem , Adulto Jovem
12.
PLoS One ; 15(9): e0239125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32991590

RESUMO

A mesoscale network model is proposed for the development of spike and wave discharges (SWDs) in the cortico-thalamo-cortical (C-T-C) circuit. It is based on experimental findings in two genetic models of childhood absence epilepsy-rats of WAG/Rij and GAERS strains. The model is organized hierarchically into two levels (brain structures and individual neurons) and composed of compartments for representation of somatosensory cortex, reticular and ventroposteriomedial thalamic nuclei. The cortex and the two thalamic compartments contain excitatory and inhibitory connections between four populations of neurons. Two connected subnetworks both including relevant parts of a C-T-C network responsible for SWD generation are modelled: a smaller subnetwork for the focal area in which the SWD generation can take place, and a larger subnetwork for surrounding areas which can be only passively involved into SWDs, but which is mostly responsible for normal brain activity. This assumption allows modeling of both normal and SWD activity as a dynamical system (no noise is necessary), providing reproducibility of results and allowing future analysis by means of theory of dynamical system theories. The model is able to reproduce most time-frequency changes in EEG activity accompanying the transition from normal to epileptiform activity and back. Three different mechanisms of SWD initiation reported previously in experimental studies were successfully reproduced in the model. The model incorporates also a separate mechanism for the maintenance of SWDs based on coupling analysis from experimental data. Finally, the model reproduces the possibility to stop ongoing SWDs with high frequency electrical stimulation, as described in the literature.


Assuntos
Epilepsia Tipo Ausência/fisiopatologia , Modelos Neurológicos , Neurônios/fisiologia , Córtex Somatossensorial/fisiopatologia , Núcleos Talâmicos/fisiopatologia , Animais , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/terapia , Masculino , Vias Neurais/fisiopatologia , Ratos , Ratos Transgênicos , Córtex Somatossensorial/citologia , Núcleos Talâmicos/citologia , Estimulação Transcraniana por Corrente Contínua/métodos
13.
Stroke ; 51(10): 3064-3073, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32883193

RESUMO

BACKGROUND AND PURPOSE: Understanding the mechanisms underlying progression/regression of symptomatic intracranial atherosclerotic stenosis (sICAS) will inform secondary prevention of the patients. Focal wall shear stress (WSS) may play an important role, which, however, had seldom been investigated. METHODS: Patients with acute ischemic stroke or transient ischemic attack (TIA) attributed to 50% to 99% intracranial atherosclerotic stenosis were recruited. All patients underwent cerebral computed tomography angiography at baseline, and a computational fluid dynamics model was built based on computed tomography angiography to simulate blood flow and quantify WSS in the vicinity of the sICAS lesion. All patients received optimal medical treatment and a second computed tomography angiography at 1 year. The change in the luminal stenosis from baseline to 1 year in sICAS was defined as progression (increased >10%), quiescence (±10%), or regression (decreased >10%). Associations between baseline WSS metrics and sICAS regression were analyzed. RESULTS: Among 39 patients (median age 62 years; 27 males), sICAS luminal stenosis progressed, remained quiescent and regressed in 6 (15.4%), 15 (38.5%), and 18 (46.2%) cases, respectively. A higher maximum WSS and larger high-WSS area, throughout the sICAS lesion or obtained separately in the proximal and distal parts of the lesion, were independently associated with regression of luminal stenosis in sICAS over 1 year. CONCLUSIONS: A majority of sICAS lesions regress or stay quiescent in the luminal stenosis over 1 year after stroke under optimal medical treatment, when higher focal WSS may facilitate stenosis regression. Further studies of the effects of hemodynamics including WSS in altering plaque vulnerability and stroke risks are needed.


Assuntos
Isquemia Encefálica/fisiopatologia , Arteriosclerose Intracraniana/fisiopatologia , Estresse Mecânico , Acidente Vascular Cerebral/fisiopatologia , Idoso , Isquemia Encefálica/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Progressão da Doença , Feminino , Humanos , Hidrodinâmica , Arteriosclerose Intracraniana/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem
14.
Phys Rev Lett ; 125(8): 088103, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32909804

RESUMO

The ability of humans and animals to quickly adapt to novel tasks is difficult to reconcile with the standard paradigm of learning by slow synaptic weight modification. Here, we show that fixed-weight neural networks can learn to generate required dynamics by imitation. After appropriate weight pretraining, the networks quickly and dynamically adapt to learn new tasks and thereafter continue to achieve them without further teacher feedback. We explain this ability and illustrate it with a variety of target dynamics, ranging from oscillatory trajectories to driven and chaotic dynamical systems.


Assuntos
Aprendizagem/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Animais , Comunicação Celular/fisiologia , Humanos , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Neurônios/citologia
15.
Nat Commun ; 11(1): 4217, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868778

RESUMO

The cerebellum plays a crucial role in sensorimotor and associative learning. However, the contribution of molecular layer interneurons (MLIs) to these processes is not well understood. We used two-photon microscopy to study the role of ensembles of cerebellar MLIs in a go-no go task where mice obtain a sugar water reward if they lick a spout in the presence of the rewarded odorant and avoid a timeout when they refrain from licking for the unrewarded odorant. In naive animals the MLI responses did not differ between the odorants. With learning, the rewarded odorant elicited a large increase in MLI calcium responses, and the identity of the odorant could be decoded from the differential response. Importantly, MLIs switched odorant responses when the valence of the stimuli was reversed. Finally, mice took a longer time to refrain from licking in the presence of the unrewarded odorant and had difficulty becoming proficient when MLIs were inhibited by chemogenetic intervention. Our findings support a role for MLIs in learning valence in the cerebellum.


Assuntos
Cerebelo/fisiologia , Condicionamento Operante/fisiologia , Interneurônios/fisiologia , Aprendizagem/fisiologia , Células de Purkinje/fisiologia , Algoritmos , Animais , Cerebelo/citologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica , Modelos Neurológicos , Odorantes , Recompensa , Fatores de Tempo
16.
PLoS One ; 15(9): e0234749, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966291

RESUMO

Traumatic brain injury (TBI) can lead to neurodegeneration in the injured circuitry, either through primary structural damage to the neuron or secondary effects that disrupt key cellular processes. Moreover, traumatic injuries can preferentially impact subpopulations of neurons, but the functional network effects of these targeted degeneration profiles remain unclear. Although isolating the consequences of complex injury dynamics and long-term recovery of the circuit can be difficult to control experimentally, computational networks can be a powerful tool to analyze the consequences of injury. Here, we use the Izhikevich spiking neuron model to create networks representative of cortical tissue. After an initial settling period with spike-timing-dependent plasticity (STDP), networks developed rhythmic oscillations similar to those seen in vivo. As neurons were sequentially removed from the network, population activity rate and oscillation dynamics were significantly reduced. In a successive period of network restructuring with STDP, network activity levels returned to baseline for some injury levels and oscillation dynamics significantly improved. We next explored the role that specific neurons have in the creation and termination of oscillation dynamics. We determined that oscillations initiate from activation of low firing rate neurons with limited structural inputs. To terminate oscillations, high activity excitatory neurons with strong input connectivity activate downstream inhibitory circuitry. Finally, we confirm the excitatory neuron population role through targeted neurodegeneration. These results suggest targeted neurodegeneration can play a key role in the oscillation dynamics after injury.


Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Simulação por Computador , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Potenciais de Ação , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Lesões Encefálicas Traumáticas/complicações , Humanos , Rede Nervosa/fisiologia , Doenças Neurodegenerativas/etiologia , Plasticidade Neuronal , Neurônios/patologia , Neurônios/fisiologia
17.
PLoS One ; 15(9): e0238054, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941475

RESUMO

Attractor neural networks such as the Hopfield model can be used to model associative memory. An efficient associative memory should be able to store a large number of patterns which must all be stable. We study in detail the meaning and definition of stability of network states. We reexamine the meanings of retrieval, recognition and recall and assign precise mathematical meanings to each of these terms. We also examine the relation between them and how they relate to memory capacity of the network. We have shown earlier in this journal that orthogonalization scheme provides an effective way of overcoming catastrophic interference that limits the memory capacity of the Hopfield model. It is not immediately apparent whether the improvement made by orthgonalization affects the processes of retrieval, recognition and recall equally. We show that this influence occurs to different degrees and hence affects the relations between them. We then show that the conditions for pattern stability can be split into a necessary condition (recognition) and a sufficient one (recall). We interpret in cognitive terms the information being stored in the Hopfield model and also after it is orthogonalized. We also study the alterations in the network dynamics of the Hopfield network upon the introduction of orthogonalization, and their effects on the efficiency of the network as an associative memory.


Assuntos
Algoritmos , Memória/fisiologia , Rememoração Mental/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Redes Neurais de Computação , Reconhecimento Psicológico , Humanos
18.
PLoS One ; 15(9): e0238397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966285

RESUMO

The development of drugs targeting the brain still faces a high failure rate. One of the reasons is a lack of quantitative understanding of the complex processes that govern the pharmacokinetics (PK) of a drug within the brain. While a number of models on drug distribution into and within the brain is available, none of these addresses the combination of factors that affect local drug concentrations in brain extracellular fluid (brain ECF). Here, we develop a 3D brain unit model, which builds on our previous proof-of-concept 2D brain unit model, to understand the factors that govern local unbound and bound drug PK within the brain. The 3D brain unit is a cube, in which the brain capillaries surround the brain ECF. Drug concentration-time profiles are described in both a blood-plasma-domain and a brain-ECF-domain by a set of differential equations. The model includes descriptions of blood plasma PK, transport through the blood-brain barrier (BBB), by passive transport via paracellular and transcellular routes, and by active transport, and drug binding kinetics. The impact of all these factors on ultimate local brain ECF unbound and bound drug concentrations is assessed. In this article we show that all the above mentioned factors affect brain ECF PK in an interdependent manner. This indicates that for a quantitative understanding of local drug concentrations within the brain ECF, interdependencies of all transport and binding processes should be understood. To that end, the 3D brain unit model is an excellent tool, and can be used to build a larger network of 3D brain units, in which the properties for each unit can be defined independently to reflect local differences in characteristics of the brain.


Assuntos
Encéfalo/metabolismo , Modelos Neurológicos , Preparações Farmacêuticas/metabolismo , Animais , Transporte Biológico Ativo , Velocidade do Fluxo Sanguíneo , Barreira Hematoencefálica/metabolismo , Encéfalo/anatomia & histologia , Encéfalo/irrigação sanguínea , Líquido Extracelular/metabolismo , Humanos , Conceitos Matemáticos , Preparações Farmacêuticas/sangue , Farmacocinética , Ratos , Distribuição Tecidual
19.
PLoS One ; 15(9): e0238586, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915814

RESUMO

Locomotion control in mammals has been hypothesized to be governed by a central pattern generator (CPG) located in the circuitry of the spinal cord. The most common model of the CPG is the half center model, where two pools of neurons generate alternating, oscillatory activity. In this model, the pools reciprocally inhibit each other ensuring alternating activity. There is experimental support for reciprocal inhibition. However another crucial part of the half center model is a self inhibitory mechanism which prevents the neurons of each individual pool from infinite firing. Self-inhibition is hence necessary to obtain alternating activity. But critical parts of the experimental bases for the proposed mechanisms for self-inhibition were obtained in vitro, in preparations of juvenile animals. The commonly used adaptation of spike firing does not appear to be present in adult animals in vivo. We therefore modeled several possible self inhibitory mechanisms for locomotor control. Based on currently published data, previously proposed hypotheses of the self inhibitory mechanism, necessary to support the CPG hypothesis, seems to be put into question by functional evaluation tests or by in vivo data. This opens for alternative explanations of how locomotion activity patterns in the adult mammal could be generated.


Assuntos
Geradores de Padrão Central/fisiologia , Inibição Psicológica , Modelos Neurológicos , Animais , Simulação por Computador , Interneurônios/fisiologia , Mamíferos/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia
20.
PLoS Comput Biol ; 16(9): e1008144, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886673

RESUMO

At the macroscale, the brain operates as a network of interconnected neuronal populations, which display coordinated rhythmic dynamics that support interareal communication. Understanding how stimulation of different brain areas impacts such activity is important for gaining basic insights into brain function and for further developing therapeutic neurmodulation. However, the complexity of brain structure and dynamics hinders predictions regarding the downstream effects of focal stimulation. More specifically, little is known about how the collective oscillatory regime of brain network activity-in concert with network structure-affects the outcomes of perturbations. Here, we combine human connectome data and biophysical modeling to begin filling these gaps. By tuning parameters that control collective system dynamics, we identify distinct states of simulated brain activity and investigate how the distributed effects of stimulation manifest at different dynamical working points. When baseline oscillations are weak, the stimulated area exhibits enhanced power and frequency, and due to network interactions, activity in this excited frequency band propagates to nearby regions. Notably, beyond these linear effects, we further find that focal stimulation causes more distributed modifications to interareal coherence in a band containing regions' baseline oscillation frequencies. Importantly, depending on the dynamical state of the system, these broadband effects can be better predicted by functional rather than structural connectivity, emphasizing a complex interplay between anatomical organization, dynamics, and response to perturbation. In contrast, when the network operates in a regime of strong regional oscillations, stimulation causes only slight shifts in power and frequency, and structural connectivity becomes most predictive of stimulation-induced changes in network activity patterns. In sum, this work builds upon and extends previous computational studies investigating the impacts of stimulation, and underscores the fact that both the stimulation site, and, crucially, the regime of brain network dynamics, can influence the network-wide responses to local perturbations.


Assuntos
Encéfalo/fisiologia , Conectoma , Modelos Neurológicos , Humanos , Neurônios/fisiologia
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