Background

Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood.

Methods

We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment.

Results

Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms.

Conclusions

Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.

中文翻译：

---

功能性大脑连接变化的转录组和细胞解码揭示了局部大脑对促炎和抗炎治疗的脆弱性

背景

全身性炎症会引起情绪、动机和认知的急性变化，这与在抑郁个体中观察到的情况非常相似。然而，通过对大脑功能的中间影响将外周炎症与抑郁样精神病理学联系起来的机制途径仍未完全了解。

方法

我们结合了来自 30 名开始使用干扰素-α 治疗丙型肝炎和 20 名抗肿瘤坏死因子 (TNF) 治疗炎症性关节炎的患者的数据，并使用静息状态功能磁共振成像来研究每种治疗对局部全球大脑连接的急性影响(GBC)。我们利用来自 Allen 人脑图谱的转录组数据来揭示潜在的生物和细胞途径，这些途径支持区域易受每种治疗诱导的 GBC 变化的影响。

结果

干扰素-α 和抗 TNF 疗法均在区域 GBC 中产生了不同的中小型下降。然而，这些是在不同的大脑区域内观察到的，并且每种治疗诱导的 GBC 变化的区域模式并不相关，表明独立的潜在过程。此外，这些不同的 GBC 减少的空间分布可以通过分别与以下相关基因的组成性区域表达的多变量模式来捕获：i) 神经炎症和神经胶质细胞；ii) 谷氨酸能神经传递和神经元。每个参与者表达与这些转录组易损性模式一致的 GBC 变化模式的程度也与急性治疗引起的白细胞介素 6 (IL-6) 和干扰素-α 的变化相关，

结论

总之，我们提出了两个转录组模型，分别将区域易感性与干扰素-α 和抗 TNF 治疗对神经胶质神经炎症和谷氨酸能神经传递的脑功能的急性影响联系起来。这些发现产生了关于两种潜在大脑机制的假设，通过这些机制，外周炎症的双向变化可能有助于精神病理学的发展/解决。