Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Medical Image Processing Laboratory, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland.
Biol Psychiatry. 2021 Jul 1;90(1):58-68. doi: 10.1016/j.biopsych.2020.12.033. Epub 2021 Jan 18.
Hippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. Moreover, there is strong translational evidence that preserving the maturation of hippocampal networks in mice models prevents the progression of cognitive deficits. However, the developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. 22q11 deletion syndrome (22q11DS) offers a unique model for characterizing early neural correlates of schizophrenia.
We acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups.
Relative to control subjects, patients with 22q11DS failed to increase HFC with frontal regions such as the dorsal part of the anterior cingulate cortex, prefrontal cortex, and supplementary motor area. Concurrently, carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. Remarkably, this aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms.
Our findings suggest a critical period of prefrontal cortex-hippocampal-striatal circuit dysmaturation, particularly during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis.
海马体的改变是精神分裂症谱系中最常见的神经影像学发现之一。此外，有强有力的转化证据表明，在小鼠模型中保护海马网络的成熟可以防止认知缺陷的进展。然而，人类群体中海马功能连接（HFC）的发育轨迹及其对精神分裂症的贡献尚不清楚。22q11 缺失综合征（22q11DS）为描述精神分裂症早期神经相关性提供了一个独特的模型。
我们在 84 名 22q11DS 患者（30 名有中度至重度阳性精神病症状）和 94 名健康对照者的年龄范围为 6 至 32 岁的 242 次重复扫描中采集了静息状态功能磁共振成像。我们获得了双侧海马体与全脑功能连接，并采用偏最小二乘相关的新的纵向多变量方法来评估 HFC 在各组中的发育轨迹。
与对照组相比，22q11DS 患者未能增加与额前区（如前扣带回皮质背侧部分、前额叶皮质和辅助运动区）的 HFC。同时，缺失载体的 HFC 与皮质下多巴胺能区域异常升高。值得注意的是，这种 HFC 的异常成熟在青春期中期更为明显，主要是由表现出亚阈值阳性精神病症状的患者驱动的。
我们的发现表明，前额叶皮质-海马体-纹状体回路不成熟的关键时期，特别是在青春期后期，根据当前的转化证据，这可能是短期干预的目标，以潜在地实现与精神病相关的回路功能障碍的长期挽救。
