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 categorial 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.Fig. 1BRAIN AREAS EXHIBITED ALTERATIONS IN ICC ANALYSIS.: a Right medial prefrontal cortex (R_MPFC); b right putamen; c left dorsolateral prefrontal cortex (L_DLPFC); d group differences in R_MPFC; e group differences in right putamen; f group differences in L_DLPFC. R_MPFC right medial prefrontal cortex, L_DLPFC left dorsolateral prefrontal cortex. For visualization, statistical maps are displayed with a threshold of p < 0.005 uncorrected.Fig. 2BRAIN REGIONS SHOWED ABERRANT FUNCTIONAL CONNECTIVITY WITH SEEDS FROM ICC.: a Altered right putamen-right amygdala (centromedial) connectivity and b post hoc group differences. ICC intrinsic connectivity contrast.Fig. 3Associations between (a) the right MPFC and depressive symptom-load; b the left DLPFC and depressive symptom load; c the right putamen and GAD symptom load; and d the right putamen-right amygdala connectivity and GAD symptom load. Scatter plots represented the entire sample pooling the data GAD, MDD, and HC. Diagnostic group membership is color-coded. Vertical axis reflects parameter estimates of corresponding brain areas. *p < 0.05; **p < 0.005, all p values FDR corrected for multiple comparisons. MPFC medial prefrontal cortex, DLPFC dorsolateral prefrontal cortex. Green = HC, blue = MDD, and red = GAD.Fig. 4NeuroSynth decoding of (a) right MPFC, (b) right putamen, and (c) left DLPFC. MPFC medial prefrontal cortex, DLPFC dorsolateral prefrontal cortex.