PDF(Pubmed)
Abstract：
Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently.
Autism is a condition that is usually diagnosed early in life that affects how a person communicates and socializes, and is often characterized by repetitive behaviors. One key theory of autism is that it reflects an imbalance in levels of excitation and inhibition in the brain. Excitatory signals are those that make other brain cells more likely to become active; inhibitory signals have the opposite effect. In non-autistic individuals, inhibitory activity outweighs excitatory activity. In people with autism, by contrast, an increase in excitatory activity is believed to produce an imbalance in excitation and inhibition. Most of the evidence to support this excitation-inhibition imbalance theory has come from studies of rare mutations that cause autism. Many of these mutations occur on the sex chromosomes or are influenced by androgen hormones (hormones that usually play a role on typically male traits). However, most people with autism do not possess these particular mutations. It was thus unclear whether the theory could apply to everyone with autism or, for example, whether it may better apply to specific groups of individuals based on their sex or gender. This is especially important given that about four times as many men and boys compared to women and girls are diagnosed with autism. Trakoshis, Martínez-Cañada et al. have now found a way to ask whether any imbalance in excitation and inhibition in the brain occurs differently in men and women. Using computer modeling, they identified a signal in brain scans that corresponds to an imbalance of excitation and inhibition. After showing that the technique works to identify real increases in excitation in the brain scans of mice, Trakoshis, Martínez-Cañada et al. looked for this signal, or biomarker, in brain scans of people with and without autism. All the people in the study identified with the gender that matched the sex they were assigned at birth. The results revealed differences between the men and women with autism. Men with autism showed an imbalance in excitation and inhibition in specific ‘social brain\' regions including the medial prefrontal cortex, but women with autism did not. Notably, many of these brain regions are strongly affected by androgen hormones. Previous studies have found that women with autism are sometimes better at hiding or ‘camouflaging’ their difficulties when socializing or communicating than men with autism. Trakoshis, Martínez-Cañada et al. showed that the better a woman was at camouflaging her autism, the more her brain activity in this region resembled that of non-autistic women. Excitation-inhibition imbalance may thus affect specific brain regions involved in socializing and communication more in men who have autism than in women with the condition. Balanced excitation and inhibition in these brain areas may enable some women with autism to camouflage their difficulties socializing or communicating. Being able to detect imbalances in activity using standard brain imaging could be useful for clinical trials. Future studies could use this biomarker to monitor responses to drug treatments that aim to adjust the balance between excitation and inhibition.
Autism is a condition that is usually diagnosed early in life that affects how a person communicates and socializes, and is often characterized by repetitive behaviors. One key theory of autism is that it reflects an imbalance in levels of excitation and inhibition in the brain. Excitatory signals are those that make other brain cells more likely to become active; inhibitory signals have the opposite effect. In non-autistic individuals, inhibitory activity outweighs excitatory activity. In people with autism, by contrast, an increase in excitatory activity is believed to produce an imbalance in excitation and inhibition. Most of the evidence to support this excitation-inhibition imbalance theory has come from studies of rare mutations that cause autism. Many of these mutations occur on the sex chromosomes or are influenced by androgen hormones (hormones that usually play a role on typically male traits). However, most people with autism do not possess these particular mutations. It was thus unclear whether the theory could apply to everyone with autism or, for example, whether it may better apply to specific groups of individuals based on their sex or gender. This is especially important given that about four times as many men and boys compared to women and girls are diagnosed with autism. Trakoshis, Martínez-Cañada et al. have now found a way to ask whether any imbalance in excitation and inhibition in the brain occurs differently in men and women. Using computer modeling, they identified a signal in brain scans that corresponds to an imbalance of excitation and inhibition. After showing that the technique works to identify real increases in excitation in the brain scans of mice, Trakoshis, Martínez-Cañada et al. looked for this signal, or biomarker, in brain scans of people with and without autism. All the people in the study identified with the gender that matched the sex they were assigned at birth. The results revealed differences between the men and women with autism. Men with autism showed an imbalance in excitation and inhibition in specific ‘social brain\' regions including the medial prefrontal cortex, but women with autism did not. Notably, many of these brain regions are strongly affected by androgen hormones. Previous studies have found that women with autism are sometimes better at hiding or ‘camouflaging’ their difficulties when socializing or communicating than men with autism. Trakoshis, Martínez-Cañada et al. showed that the better a woman was at camouflaging her autism, the more her brain activity in this region resembled that of non-autistic women. Excitation-inhibition imbalance may thus affect specific brain regions involved in socializing and communication more in men who have autism than in women with the condition. Balanced excitation and inhibition in these brain areas may enable some women with autism to camouflage their difficulties socializing or communicating. Being able to detect imbalances in activity using standard brain imaging could be useful for clinical trials. Future studies could use this biomarker to monitor responses to drug treatments that aim to adjust the balance between excitation and inhibition.
摘要：
兴奋抑制（E：I）失衡被认为是自闭症的重要病理生理机制。自闭症影响男性的频率高于女性和性别相关机制(例如，X连锁基因，雄激素激素）可以影响E：I平衡。这表明E：I失衡可能会对男性和女性的自闭症产生不同的影响。结合计算机建模和小鼠体内化学遗传学操作，我们首先展示了从fMRIBOLD信号估计的时间序列度量，赫斯特指数(H)，可以是突触E:I比率的潜在变化的指标。在自闭症中，我们发现H降低，指示增加的激励，在自闭症男性而非女性的内侧前额叶皮层（MPFC）中。越来越完整的MPFCH也与行为伪装社会交际困难的能力增强有关，但仅限于自闭症女性。这项工作表明，BOLD中的H可以索引突触E：I比率，并且E：I失衡对自闭症男性和女性的影响不同。
自闭症是一种通常在生命早期诊断的疾病，会影响一个人的沟通和社交方式，通常以重复行为为特征。自闭症的一个关键理论是，它反映了大脑兴奋和抑制水平的不平衡。兴奋信号是那些使其他脑细胞更有可能变得活跃的信号；抑制信号具有相反的作用。在非自闭症患者中，抑制活性超过兴奋性活性。在自闭症患者中，相比之下,兴奋活动的增加被认为会产生兴奋和抑制的不平衡。支持这种兴奋-抑制失衡理论的大多数证据都来自对导致自闭症的罕见突变的研究。这些突变中的许多突变发生在性染色体上或受雄激素激素（通常对典型的男性性状起作用的激素）的影响。然而,大多数自闭症患者不具有这些特殊的突变。因此，尚不清楚该理论是否适用于自闭症患者或，例如,它是否可能更好地适用于基于性别或性别的特定群体。这一点尤其重要，因为与女性和女孩相比，男性和男孩的比例是女性和女孩的四倍。Trakoshis,马丁内斯-卡纳达等人。现在已经找到了一种方法来询问大脑中兴奋和抑制的不平衡是否在男性和女性中发生不同的情况。利用计算机建模，他们在脑部扫描中发现了一个信号，该信号对应于兴奋和抑制的不平衡。在证明该技术可以在小鼠的大脑扫描中识别出兴奋的真正增加之后，Trakoshis,马丁内斯-卡纳达等人。寻找这个信号，或生物标志物，在患有和不患有自闭症的人的大脑扫描中。研究中的所有人都确定了与出生时分配的性别相匹配的性别。结果揭示了自闭症男女之间的差异。患有自闭症的男性在包括内侧前额叶皮层在内的特定“社会大脑”区域表现出兴奋和抑制的失衡，但是自闭症女性没有。值得注意的是,许多这些脑区受到雄激素激素的强烈影响。先前的研究发现，自闭症女性在社交或交流时有时比自闭症男性更好地隐藏或“伪装”她们的困难。Trakoshis,马丁内斯-卡纳达等人。表明一个女人越善于伪装她的自闭症，她在这个区域的大脑活动就越像非自闭症女性。因此，与自闭症患者相比，自闭症患者的兴奋抑制失衡可能会更多地影响参与社交和交流的特定大脑区域。这些大脑区域的平衡兴奋和抑制可能使一些自闭症女性伪装她们在社交或沟通方面的困难。能够使用标准脑成像检测活动的不平衡可能对临床试验有用。未来的研究可以使用这种生物标志物来监测对药物治疗的反应，旨在调整兴奋和抑制之间的平衡。
自闭症是一种通常在生命早期诊断的疾病，会影响一个人的沟通和社交方式，通常以重复行为为特征。自闭症的一个关键理论是，它反映了大脑兴奋和抑制水平的不平衡。兴奋信号是那些使其他脑细胞更有可能变得活跃的信号；抑制信号具有相反的作用。在非自闭症患者中，抑制活性超过兴奋性活性。在自闭症患者中，相比之下,兴奋活动的增加被认为会产生兴奋和抑制的不平衡。支持这种兴奋-抑制失衡理论的大多数证据都来自对导致自闭症的罕见突变的研究。这些突变中的许多突变发生在性染色体上或受雄激素激素（通常对典型的男性性状起作用的激素）的影响。然而,大多数自闭症患者不具有这些特殊的突变。因此，尚不清楚该理论是否适用于自闭症患者或，例如,它是否可能更好地适用于基于性别或性别的特定群体。这一点尤其重要，因为与女性和女孩相比，男性和男孩的比例是女性和女孩的四倍。Trakoshis,马丁内斯-卡纳达等人。现在已经找到了一种方法来询问大脑中兴奋和抑制的不平衡是否在男性和女性中发生不同的情况。利用计算机建模，他们在脑部扫描中发现了一个信号，该信号对应于兴奋和抑制的不平衡。在证明该技术可以在小鼠的大脑扫描中识别出兴奋的真正增加之后，Trakoshis,马丁内斯-卡纳达等人。寻找这个信号，或生物标志物，在患有和不患有自闭症的人的大脑扫描中。研究中的所有人都确定了与出生时分配的性别相匹配的性别。结果揭示了自闭症男女之间的差异。患有自闭症的男性在包括内侧前额叶皮层在内的特定“社会大脑”区域表现出兴奋和抑制的失衡，但是自闭症女性没有。值得注意的是,许多这些脑区受到雄激素激素的强烈影响。先前的研究发现，自闭症女性在社交或交流时有时比自闭症男性更好地隐藏或“伪装”她们的困难。Trakoshis,马丁内斯-卡纳达等人。表明一个女人越善于伪装她的自闭症，她在这个区域的大脑活动就越像非自闭症女性。因此，与自闭症患者相比，自闭症患者的兴奋抑制失衡可能会更多地影响参与社交和交流的特定大脑区域。这些大脑区域的平衡兴奋和抑制可能使一些自闭症女性伪装她们在社交或沟通方面的困难。能够使用标准脑成像检测活动的不平衡可能对临床试验有用。未来的研究可以使用这种生物标志物来监测对药物治疗的反应，旨在调整兴奋和抑制之间的平衡。
