GABAergic cortical network physiology in frontotemporal lobar degeneration.
GABAergic cortical network physiology in frontotemporal lobar degeneration.
复制标题
GABA能皮质网络生理学的额颞叶变性。
DOI：
10.1093/brain/awab097
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发表时间：
2021-08-17
期刊：
影响因子：
--
通讯作者：
Rowe JB
中科院分区：
文献类型：
--
作者：
Adams NE;Hughes LE;Rouse MA;Phillips HN;Shaw AD;Murley AG;Cope TE;Bevan-Jones WR;Passamonti L;Street D;Holland N;Nesbitt D;Friston K;Rowe JB
额颞叶变性引起的临床综合征多种多样，包括行为变异型额颞叶痴呆（bvFTD）和进行性核上性麻痹。尽管病理上不同，但它们具有许多行为、认知和生理特征，部分原因可能是由于γ-氨基丁酸（GABA）等主要神经递质的共同缺陷所致。在这里，我们通过双盲安慰剂对照交叉药物脑磁图研究的动态因果模型来量化 GABA 能损伤及其恢复。我们分析了 17 名 bvFTD 患者、15 名进行性核上性麻痹患者以及 20 名年龄和性别匹配的健康对照者。除了神经心理学评估和结构 MRI 之外，参与者还使用流动听觉奇怪范式进行了两次脑磁图检查：一次服用安慰剂，另一次服用 10 毫克口服 GABA 再摄取抑制剂噻加宾。一个亚组接受了超高场磁共振波谱法测量 GABA 浓度，发现患者的 GABA 浓度有所降低。我们使用基于电导的局部和全局神经元网络生物物理模型确定了额颞处理的缺陷。这种生理缺陷的临床相关性通过从额叶到颞叶皮层的自上而下的连接与认知和行为变化的临床测量之间的相关性来表明。生物物理建模方法的一个关键验证是来自参数经验贝叶斯分析的证据，即通过光谱测量的患者 GABA 水平与患者 GABA 能突触连接的后验估计相关。 GABA 在额颞叶变性中的作用的进一步证据来自于确认噻加宾对局部回路的影响不仅取决于参与者组，还取决于个体基线 GABA 水平。具体而言，噻加宾（而非安慰剂）后深部皮质-皮质锥体神经元的阶段性抑制是 GABA 浓度的函数。该研究为动态因果模型阐明人类神经退行性疾病机制的潜力提供了概念验证，并解释了患者对候选疗法反应的差异。建模框架的层流和神经递质特异性特征可用于研究其他治疗方法和疾病。在额颞叶变性的背景下，我们建议，通过针对神经递质缺陷，对选定患者进行神经生理学恢复，可用于在疾病的临床和临床前模型之间建立桥梁，并为未来临床试验的药物个性化选择和患者分层提供信息。 Adams 等人使用来自对照组和 FTLD 患者的数据的生物物理模型，在使用和关闭 GABA 能药物的情况下，结合 GABA 光谱学，Adams 等人。研究表明，神经退行性变中神经传递的潜在恢复取决于基线生理学破坏的程度。
The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials. Using biophysical modelling of data from controls and FTLD patients, on and off a GABAergic drug, combined with GABA spectroscopy, Adams et al. show that the potential restoration of neurotransmission in neurodegeneration depends on the degree of disruption to baseline physiology.
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影响因子：
16.2
作者：
Bastos AM;Usrey WM;Adams RA;Mangun GR;Fries P;Friston KJ
通讯作者：
Friston KJ
DOI：
10.1523/jneurosci.0460-12.2012
发表时间：
2012-08-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Duguid I;Branco T;London M;Chadderton P;Häusser M
通讯作者：
Häusser M
DOI：
10.1097/00005072-199904000-00006
发表时间：
1999-04-01
影响因子：
3.2
作者：
Bigio, EH;Brown, DF;White, CL
通讯作者：
White, CL
DOI：
10.1016/j.bpsc.2019.10.011
发表时间：
2020-03-01
影响因子：
5.9
作者：
Aponte, Eduardo A.;Schobi, Dario;Heinzle, Jakob
通讯作者：
Heinzle, Jakob
影响因子：
5.7
作者：
Friston, Karl J.;Mattout, Jeremie;Penny, Will
通讯作者：
Penny, Will