Investing mental effort is costly, and the investment has to be matched by a reward to make a person engage in task performance. However, the neural structures underlying the continued management of mental effort are not known. Previous work has identified left-lateralized structures, most prominently the left anterior Insular Cortex (aIC) as regions implied in post-hoc evaluation and also anticipation of mental effort investment. We present a study aimed at identifying neural structures that are sensitive to changes in both task load and fatigue-induced state load. Sixteen healthy participants performed an n-back task before and after a fatigue-inducing day in a helicopter simulator or a free day. Subjective mental effort ratings showed an interaction of the effects of both task and state load changes, with a reduced effect of task load during the fatigued state. Testing for the same interaction effect in a whole-brain functional MRI data, we found a left-lateralized group of clusters in aIC, the anterior cingulate cortex, the dorsal striatum and frontal eye field and M1. We discuss the possible role of these areas and also the relevance of our findings in the light of the proposed opportunity cost model of mental effort.