Disorders of consciousness (DOC) raise profound scientific, clinical, ethical, and philosophical issues. Growing knowledge on fundamental principles of brain organization in healthy individuals offers new opportunities for a better understanding of residual brain function in DOCs. We here discuss new perspectives derived from a recently proposed scheme of brain organization underlying consciousness in healthy individuals. In this scheme, thalamo-cortical networks can be divided into two, often antagonistic, global systems: (i) a system of externally oriented, sensory-motor networks (the ‘‘extrinsic’’ system); and (...) (ii) a system of inward-oriented networks (the ‘‘intrinsic’’ or default system). According to this framework, four distinct mental states would be possible that could be relevant for understanding DOCs. In normal healthy volunteers and locked-in syndrome patients, a state of high functionality of both the extrinsic and intrinsic or default systems is expected — associated with full awareness of environment and self. In this case, mental imagery tasks combined with fMRI can be used to detect covert awareness in patients that are unable to communicate. According to the framework, two complementary states of system imbalance are also possible, in which one system is in a hyperfunctional state, while the other is hypoactive. Extrinsic system hyperfunction is expected to lead to a state of total sensory-motor ‘‘absorption’’ or ‘‘lost self.’’ In contrast, intrinsic or default system hyperfunction is expected to lead to a state of complete detachment from the external world. A state where both extrinsic and intrinsic systems are hypofunctional is predicted to lead to markedly impaired consciousness as seen in DOCs. Finally, we review the potential use of ultra-slow fluctuations in BOLD signal as a tool for assessing the functional integrity of extrinsic and intrinsic systems during ‘‘resting state’’ fMRI acquisitions.. (shrink)