Miyakoshi Makoto, Kim Hyeonseok, De Stefano Lisa A, Schmitt Lauren M, Norris Jordan E, Ethridge Lauren E, Erickson Craig A, Pedapati Ernest V
Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States.
Cereb Cortex. 2025 Jun 4;35(6). doi: 10.1093/cercor/bhaf141.
Auditory hypersensitivity is a well-established phenotype of Fragile X syndrome (FXS), but how it relates to neurobehavioral biomarkers remains poorly understood. To offer an integrated model, we propose a dual thalamic framework with hypo-lemniscal (LEM) and hyper-extralemniscal (EXLEM) thalamic models. Traditional FXS studies may have been conflating LEM and EXLEM systems, misrepresenting the origins of the hypersensitivity. We hypothesize that hyper-EXLEM pathology impacts FXS symptoms more. To test this hypothesis, we first review the dual thalamic systems and then demonstrate the hypo-LEM and hyper-EXLEM models in individuals with FXS. We use a 40 Hz auditory steady-state response (ie LEM responses) paradigm with relatively long (1.5 to 3 s) stimulus and interstimulus intervals to evoke N1/P2 as Vertex Potentials (VPs, ie EXLEM responses) for onset and offset of the stimulus. We analyzed electroencephaogram (EEG) responses from 29 FXS and 33 healthy comparison individuals. Results showed lower intertrial coherence (ITC) in FXS, consistent with hypo-LEM predictions, and larger vertex potentials consistent with hyper-EXLEM predictions. Correlation analyses revealed that enhanced VPs classified FXS males more sensitively than ITC. These findings indicate that hyperreactivity of the EXLEM system is more dominantly related to FXS, which can provide a more accurate account for guiding diagnostic and therapeutic strategies.
听觉超敏是脆性X综合征（FXS）一种已被充分证实的表型，但它与神经行为生物标志物之间的关系仍知之甚少。为了提供一个综合模型，我们提出了一个双丘脑框架，包括低丘系（LEM）和高丘系外（EXLEM）丘脑模型。传统的FXS研究可能混淆了LEM和EXLEM系统，从而错误地描述了超敏反应的起源。我们假设EXLEM系统亢进的病理变化对FXS症状的影响更大。为了验证这一假设，我们首先回顾了双丘脑系统，然后在FXS患者中展示了低LEM和高EXLEM模型。我们使用40Hz听觉稳态反应（即LEM反应）范式，采用相对较长（1.5至3秒）的刺激和刺激间隔时间，以诱发N1/P2作为刺激开始和结束时的顶点电位（VPs，即EXLEM反应）。我们分析了29名FXS患者和33名健康对照者的脑电图（EEG）反应。结果显示，FXS患者的试验间相干性（ITC）较低，这与低LEM预测一致，而顶点电位较大，与高EXLEM预测一致。相关性分析显示，增强的VPs对FXS男性的分类比ITC更敏感。这些发现表明，EXLEM系统的反应过度与FXS的关系更为密切，这可以为指导诊断和治疗策略提供更准确的依据。
