GABA-ergic dynamics in human frontotemporal networks confirmed by pharmaco-magnetoencephalography
GABA-ergic dynamics in human frontotemporal networks confirmed by pharmaco-magnetoencephalography
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药物脑磁图证实人类额颞叶网络中的 GABA 能动力学
DOI：
10.1101/803924
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Adams N
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文献类型：
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作者：
Adams N
为了弥合疾病的临床前细胞模型和人类认知网络动态的体内成像之间的差距，迫切需要信息丰富的生物物理模型。在这里，我们评估动态因果模型（DCM）的皮层网络反应，作为生成模型的脑磁图观察在健康成年人的听觉oddball漫游范式。这种模式引起强大的扰动，渗透额颞叶网络，包括诱发的“不匹配负性”的反应和瞬态引起的振荡。在这里，我们使用GABA再摄取抑制剂噻加宾（口服，10 mg）的双盲安慰剂对照随机交叉给药，在健康老年人的网络中探测GABA能的影响。我们证明了设施的电导为基础的神经质量平均场模型，将当地的突触连接，调查板层特异性和GABA能机制的听觉反应。神经元模型准确地概括了所观察到的脑磁图数据。使用参数经验贝叶斯最佳模型反演在两个药物会话，我们确定了噻加宾的GABA能调制的深锥体和神经元间细胞群的影响。我们发现了一个过渡的主要GABA能药物的影响，从听觉皮层在标准的试验中，前额叶皮层的偏差试验。药物脑磁图与额颞叶网络的动态因果模型的成功整合提供了一个潜在的平台，在其上评估疾病和药物干预的影响。重要声明理解人脑功能和开发新的治疗方法需要良好的脑功能模型。我们测试了一个详细的生成模型的皮质微电路，准确地再现人类脑磁图，量化网络动态和连接额颞叶皮层。这种方法确定了测试药物（GABA再摄取抑制剂，噻加宾）对神经元功能（GABA能动力学）的影响，为健康和疾病的精神药理学研究开辟了道路，其机制精确度由大脑的生成模型提供。
To bridge the gap between preclinical cellular models of disease andin vivoimaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENTUnderstanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain.