King Victoria L, Hellemann Gerhard, Lahti Adrienne C, Defenderfer Matthew, Glausier Jill R, Zhang Hui, Kraguljac Nina V
Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Neuropsychopharmacology. 2025 May 23. doi: 10.1038/s41386-025-02137-9.
While white matter myelin primarily functions to accelerate conduction velocity and has been extensively studied in schizophrenia-spectrum disorders (SSD), less is known about the role of gray matter myelin in SSD. Cortical myelination occurs mostly on the proximal axons of parvalbumin positive (PV+) interneurons, where it assists in trophic support and experience-dependent plasticity. Given the role of PV+ interneuron dysfunction in SSD, it is critical to advance our understanding of cortical myelin pathology in this context. Here, we quantified myelin maps using the T1w/T2w ratio in a large group of antipsychotic medication-naïve, first-episode psychosis patients. We compared myelin content between patients (N = 91) and controls (N = 107) using a MANCOVA and calculated zero-order correlations with the discriminant function for each region, then used a machine learning approach to identify the most parsimonious constellation of cortical regions driving group differences using a stepwise algorithm. Group membership was significantly associated with T1w/T2w ratio (Wilks Lambda = 0.09, p < 0.01), where patients had higher myelin values compared to healthy controls. We identified a subset of 16 regions, primarily located in association cortices, that were sufficient to explain group differences. Here, we report an increase in the cortical T1w/T2w ratio in association cortices in first-episode psychosis. We suggest that faulty myelin compaction during this critical developmental period could contribute to PV+ interneuron pathology and cortical microcircuit disruptions resulting in the clinical phenotype. With additional empirical support from future studies, novel treatment strategies targeting cortical myelin could have potential to mitigate circuit dysfunction in the illness.
虽然白质髓鞘主要功能是加速传导速度，并且在精神分裂症谱系障碍（SSD）中已得到广泛研究，但关于灰质髓鞘在SSD中的作用却知之甚少。皮质髓鞘形成主要发生在小白蛋白阳性（PV+）中间神经元的近端轴突上，在那里它有助于营养支持和经验依赖性可塑性。鉴于PV+中间神经元功能障碍在SSD中的作用，在这种情况下推进我们对皮质髓鞘病理的理解至关重要。在这里，我们使用T1w/T2w比率对一大群未服用抗精神病药物的首发精神病患者的髓鞘图谱进行了量化。我们使用多因素协方差分析比较了患者（N = 91）和对照组（N = 107）之间的髓鞘含量，并计算了每个区域与判别函数的零阶相关性，然后使用机器学习方法通过逐步算法识别驱动组间差异的最简约的皮质区域组合。组归属与T1w/T2w比率显著相关（威尔克斯Lambda = 0.09，p < 0.01），患者的髓鞘值高于健康对照组。我们确定了16个区域的子集，主要位于联合皮质，足以解释组间差异。在这里，我们报告首发精神病患者联合皮质中皮质T1w/T2w比率增加。我们认为，在这个关键的发育时期髓鞘压实错误可能导致PV+中间神经元病理和皮质微电路破坏，从而导致临床表型。有了未来研究的更多实证支持，针对皮质髓鞘的新型治疗策略可能有减轻该疾病中电路功能障碍的潜力。
