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Intrinsic connectivity of the prefrontal cortex and striato-limbic system respectively differentiate major depressive from generalized anxiety disorder


Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are highly prevalent and debilitating disorders. The high overlap on the symptomatic and neurobiological level led to ongoing debates about their diagnostic and neurobiological uniqueness. The present study aims to identify common and disorder-specific neuropathological mechanisms and treatment targets in MDD and GAD. To this end we combined categorical and dimensional disorder models with a fully data-driven intrinsic network-level analysis (intrinsic connectivity contrast, ICC) to resting-state fMRI data acquired in 108 individuals (n = 35 and n = 38 unmedicated patients with first-episode GAD, MDD, respectively, and n = 35 healthy controls). Convergent evidence from categorical and dimensional analyses revealed MDD-specific decreased whole-brain connectivity profiles of the medial prefrontal and dorsolateral prefrontal cortex while GAD was specifically characterized by decreased whole-brain connectivity profiles of the putamen and decreased communication of this region with the amygdala. Together, findings from the present data-driven analysis suggest that intrinsic communication of frontal regions engaged in executive functions and emotion regulation represent depression-specific neurofunctional markers and treatment targets whereas dysregulated intrinsic communication of the striato-amygdala system engaged in reinforcement-based and emotional learning processes represent GAD-specific markers.

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Fig. 1: Brain areas exhibited alterations in ICC analysis.
Fig. 2: Brain regions exhibiting aberrant functional connectivity with seeds from ICC.
Fig. 3: Associations between neural indices and symptom load.
Fig. 4: Word clouds visualizing the functional characterization of the identified brain regions.


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Author information




XX, BB, and KMK designed the experiment. XX prepared the study protocols and procedures. BZ, JD, ZZ, YH, and JW performed the clinical assessments. XX, YC, CL, and FX acquired data. XX, FZ, XZ, EAS, LL, BB, and SY analyzed the data. XX, BB, KMK, DV, and EAS interpreted the data and drafted the paper. All authors commented on and gave final approval to the final version of the paper.

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Correspondence to Bo Zhou or Benjamin Becker.

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Xu, X., Dai, J., Chen, Y. et al. Intrinsic connectivity of the prefrontal cortex and striato-limbic system respectively differentiate major depressive from generalized anxiety disorder. Neuropsychopharmacol. 46, 791–798 (2021).

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