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Human cognition flexibly guides decision-making in familiar and novel situations. Although these decisions are often treated as dichotomous, in reality, situations are neither completely familiar, nor entirely new. Contemporary accounts of brain organization suggest that neural function is organized along a connectivity gradient from unimodal regions of sensorimotor cortex, through executive regions to transmodal default mode network. We examined whether this graded view of neural organization helps to explain how decision-making changes across situations that vary in their alignment with long-term knowledge. We used a semantic judgment task, which parametrically varied the global semantic similarity of items within a feature matching task to create a ‘task gradient’, from conceptual combinations that were highly overlapping in long-term memory to trials that only shared the goal-relevant feature. We found the brain's response to the task gradient varied systematically along the connectivity gradient, with the strongest response in default mode network when the probe and target items were highly overlapping conceptually. This graded functional change was seen in multiple brain regions and within individual brains, and was not readily explained by task difficulty. Moreover, the gradient captured the spatial layout of networks involved in semantic processing, providing an organizational principle for controlled semantic cognition across the cortex. In this way, the cortex is organized to support semantic decision-making in both highly familiar and less familiar situations.

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