Kranz Devorah, Braverman Yael, McCarthy Michelle, Mackay Claire, Sabol Karen, Benke Tim A, Lieberman David, Marsh Eric D, Neul Jeffrey L, Peck Fleming, Percy Alan K, Saby Joni, Kopell Nancy, Nelson Charles A, Levin April R, Fagiolini Michela
medRxiv. 2025 Jul 22:2025.07.21.25331927. doi: 10.1101/2025.07.21.25331927.
Rett syndrome is a rare neurodevelopmental disorder caused primarily by pathogenic variants in the gene, leading to lifelong cognitive impairments. To understand the broad neural disruptions in Rett syndrome, it is essential to examine large-scale brain dynamics at the level of neural oscillations. Phase-amplitude coupling-a form of cross-frequency interaction that supports information integration across temporal and spatial scales-is a promising candidate measure for capturing such widespread neural dysfunction. Phase-amplitude coupling depends on the coordinated activity of specific neuronal subtypes, and while multiple subtypes are implicated in different aspects of the Rett syndrome phenotype, their role in shaping large-scale oscillatory dynamics in Rett syndrome is not well understood. To investigate this, we utilized a multi-level approach, combining EEG recordings with computational modeling to identify alterations in phase-amplitude coupling in Rett syndrome and probe their underlying cellular and circuit-level mechanisms.
We recorded resting-state EEG from 38 individuals with Rett syndrome and 30 age- and sex-matched typically developing individuals. Phase-amplitude coupling was quantified: modulation index was obtained to determine coupling strength, and phase bias was assessed to examine the preferred phase of coupling. We characterized phase-amplitude coupling across all low and high frequency combinations and electrodes, as well as within canonical theta-gamma and alpha-gamma frequency pairs across four predefined cortical regions. Finally, we modeled a biophysically-constrained Layer 4 cortical network to propose a possible mechanism underlying changes to oscillatory dynamics.
We found significantly stronger phase-amplitude coupling in Rett syndrome across widespread cortical regions and frequency pairs, with a pronounced increase in theta-gamma and alpha-gamma coupling in anterior, posterior, and whole-brain regions ( < 0.05). Individuals with Rett syndrome also exhibited a more positive alpha-gamma phase bias in anterior and whole-brain regions ( < 0.05). Biophysically constrained modelling demonstrated that reduced VIP-expressing interneuron activity alone could recapitulate the pattern of increased theta-gamma and alpha-gamma phase-amplitude coupling observed in Rett syndrome ( < 0.001).
These findings identify alterations in awake-state phase-amplitude coupling in Rett syndrome and propose a mechanistic link to VIP+ interneuron dysfunction. Elevated phase-amplitude coupling may serve as a promising biomarker of cortical dysfunction and a translational bridge from neural circuitry to clinically observable EEG signatures. By implicating VIP+ interneurons, our results open new avenues for testing interventions in preclinical models to identify potential novel therapeutic targets for individuals with Rett syndrome.
雷特综合征是一种罕见的神经发育障碍，主要由该基因的致病变异引起，导致终身认知障碍。为了了解雷特综合征中广泛的神经紊乱，在神经振荡水平上检查大规模脑动力学至关重要。相位-振幅耦合——一种支持跨时间和空间尺度信息整合的交叉频率相互作用形式——是捕捉这种广泛神经功能障碍的一个有前景的候选指标。相位-振幅耦合取决于特定神经元亚型的协调活动，虽然多种亚型与雷特综合征表型的不同方面有关，但它们在塑造雷特综合征大规模振荡动力学中的作用尚不清楚。为了研究这一点，我们采用了一种多层次方法，将脑电图记录与计算建模相结合，以识别雷特综合征中相位-振幅耦合的改变，并探究其潜在的细胞和电路水平机制。
我们记录了38名雷特综合征患者和30名年龄和性别匹配的典型发育个体的静息态脑电图。对相位-振幅耦合进行了量化：获得调制指数以确定耦合强度，并评估相位偏差以检查耦合的偏好相位。我们对所有低频和高频组合以及电极之间的相位-振幅耦合进行了表征，以及在四个预定义皮质区域内的典型θ-γ和α-γ频率对之间进行了表征。最后，我们对一个生物物理约束的第4层皮质网络进行建模，以提出振荡动力学变化的可能机制。
我们发现雷特综合征患者在广泛的皮质区域和频率对中相位-振幅耦合明显更强，在前部、后部和全脑区域，θ-γ和α-γ耦合显著增加（<0.05）。雷特综合征患者在前部和全脑区域也表现出更正向的α-γ相位偏差（<0.05）。生物物理约束建模表明，仅降低表达血管活性肠肽（VIP）的中间神经元活动就能重现雷特综合征中观察到的θ-γ和α-γ相位-振幅耦合增加的模式（<0.001）。
这些发现确定了雷特综合征清醒状态下相位-振幅耦合的改变，并提出了与VIP+中间神经元功能障碍的机制联系。升高的相位-振幅耦合可能是皮质功能障碍的一个有前景的生物标志物，以及从神经电路到临床可观察到的脑电图特征的转化桥梁。通过涉及VIP+中间神经元，我们的结果为在临床前模型中测试干预措施开辟了新途径，以确定雷特综合征患者潜在的新治疗靶点。
