The eye structure (lenses plus a molecular detector of photons equal or comparable to rhodopsin) is an ancient contrivance remarkably invariant over time and across animal species. Double-structured lenses optically corrected in full accord with constructions by Des Carts and Huygens and the laws of optics appeared with Trilobites in early Cambrian [1]. The living fossil Limulus polyphemus began featuring retinal mechanisms of lateral inhibition and recurrent interaction (equivalent to those allowing higher mammals to identify objects) in early Triassic, long before the development of brain structures with matching functional complexity [2]¹. The sophistication of these early components the visual system exemplifies how nature can be conservative about efficient implements even when not yet usable to their full potential.

Individual consciousness seems instead to have evolved late in the progression from low- to higher-order brain organization. Children spontaneously learn self-recognition in front of a mirror at about 18 mo. of age [3]; among mammals, only young chimpanzees (4.5–8 years) can be trained to this task, and the evidence with dolphins remains unclear [4]. The mirror test marks the obvious in the child, i.e., the emergence of higher brain functions and cognitive processes we associate with consciousness; its reliability in animal investigation is by contrast questioned. Methodological issues aside, the declining of self-recognition with adulthood in the chimpanzee suggests learning processes rather than self-awareness [3, 5]. Nonhuman primates and cetacean brains seem to have evolved to levels of complexity not too dissimilar from ours. However, the (individual and collective) adaptation to environmental requirements and the cognitive, social, and intellectual developments of humankind stand as unique, while in no other species there is evidence of conscious continuity with the past and planning for the future comparable to humans. Evidence of animal consciousness is intrinsically difficult to detect, and the hypothesis is often dismissed as a false problem no matter how ancient the neurophysiological processes thought to support consciousness in humans. Markers of evolution, nosographic criteria, and underlying physiological processes need to be unambiguously identified in approaching questions such as these, in order to qualitatively and quantitatively define consciousness (and its possible different states or levels) in a general taxonomy independent of self-experiencing, verbal reporting, and cultural biases [6–23].

Research on consciousness focuses mostly on cortical/brain activation, network complexity, long-range connectivity, neuronal synchronization in selected frequency ranges, uni/multimodal perception, motor activation, etc. Consciousness is thought to result of large-scale information processing and neurobiological mechanisms [24–28], as opposed to hypotheses assimilating consciousness and conscious perception [29] that are based on evidence of regionally mediated synchronization between large neuronal populations of distinct areas during conscious perception [24, 30]. Sensory inflow and sensorimotor integration, brainstem activating ascending systems, thalamocortical interaction, primitive motor systems, metabolic supply, and neuromodulation balance are crucial [31]. Synchronization in the gamma-band frequency range is thought to be a mechanism for bottom-up activation of neuronal assemblies [32–37] and is reportedly maintained in disorders of consciousness (DoC) when top-down synchronization appears lost [38]. However, the contributions of these processes in sustaining consciousness are defined indirectly by the effects of damage. The extent to which surgical anesthesia actually affects consciousness remains poorly understood, with different pharmacological mechanisms of drug action apparently inducing the same main effect [39–43]. Sleep mechanisms evolved early and are ancient: the patterns of brain activation and network functional organization which sustain wakefulness, non-REM sleep, and REM sleep are incompatible to each other [44, 45], but we remain ourselves and self-conscious also in the most unrealistic dream and even happen to be aware of our dreaming [46]. The variety of brain mechanisms thought to contribute in sustaining consciousness (and the impairment of which results in DoC) has implication in neuroscience in suggesting that it results of a complex functional arrangement interacting with but distinct from all other higher brain processes (e.g., attention) [9, 28, 47–49]. In this respect, the master unsolved problem pervading neuroscience remains how the combination of billions of robust individual components (neurons) with flexible weak linkages between regulatory processes works together to create brain functions, including consciousness [50, 51].

Neuroimaging has documented residual high-level aspects of brain activity across sensory modalities, language and learning dynamics, emotions, or pain also in subjects otherwise diagnosed as being in vegetative state/unresponsive wakefulness syndrome (VS/UWS) [52, 53]. Responses varied in complexity, from local activation of primary sensory cortices, to the involvement of associative areas, to activation of cortical-subcortical networks to either mental imagery tasks or distinction of ambiguous/nonambiguous words [16, 54–68]. Retained connectivity in segregated networks provides evidence of the severely damaged brain capability to express surviving modular functions that do not necessarily give rise to phenomenological awareness, in the absence of the integrative processes deemed necessary to consciousness [65, 69]. This has been understood as indicative of residual covert cognition or consciousness as opposed to alternative interpretations that markers of neural activity not necessarily are surrogates for these functions [63, 70–76]. The surviving networks observed in these studies compare as to anatomy and modes of activation to those observable in healthy subjects under comparable conditions. The similarity validates the hypothesis that stimulus- or condition-related regional brain activations do not occur at random in DoC. It also reinforces the evidence that neuronal and network mechanisms of the brain (mediating, e.g., in sensory data processing or motor action) can operate with limited or null interference from conscious processes [77–81].

Brain activation reflecting some awareness and cognition was observed by neuroimaging in only a small number of subjects [61]. The preservation of specific neural structures and available residual functional resources has been suggested to vary because of the heterogeneity of etiology and pathophysiology or extension and severity of brain damage [82]. Individual variability aside, the reports of subjects classified as being in VS/UWS according to clinical protocols who have proven able to produce voluntary “brain behavior” suggestive of partially retained consciousness during neuroimaging or neurophysiologic assessments [53, 61, 62, 83, 84] cannot be easily dismissed.

Neurophysiology and neuroimaging have rapidly become alternative methodological approaches, and results proved scientifically seminal. These technologies have revolutionized our understanding of DoC and emphasized the possible relationship between brain response and consciousness. A general discussion is currently underway in the scientific and clinical communities concerning the meaning of regional brain activations in DoC, the circumstances under which brain responsiveness should be considered equivalent to consciousness, and the reliability of brain activations as a marker of consciousness [60, 85, 86]. The current definitions and traditional understanding of both responsiveness and consciousness are being challenged. The focus is on whether this line of scientific evidence may result misleading in research on the lower boundaries of consciousness [15]. It is also a matter of discussion whether patients who clinically fulfill the clinical criteria for VS/UWS but show regional brain responses should be considered conscious nonetheless and which is the acceptable discrepancy between clinical and neuroscientific evidence. According to the international guidelines [76, 87–91], the observation of each aspect of consciousness is based on the detection of recognizable behavioral signs, including sustained cycles of eye-opening. While practical in the clinical environment, retrospective audits and studies comparing diagnostic protocols have consistently reported a high rate of misdiagnosis between the VS/UWS and minimally conscious state (MCS) [67, 92–94]. Individual variability, either spontaneous or reflecting changes in the neuronal or non-neuronal factors modulating the brain functional state [95], appears relevant in DoC and should be taken in proper account when testing responsiveness [96, 97].

The very clinical standards by which patients are classified as conscious or unconscious have also been called into question. In the clinical community, the resulting dichotomy between traditional criteria based on observation (currently the golden standard) and evidence from advanced neuroimaging research is creating difficulties in the patient’s diagnosis and early prognosis. Neurologists are confronted with unresolved issues that involve pain, sensory or emotional/affective responsiveness, and predictability of recovery and vex both the patients’ families and the health team. The responsibility of diagnosis and early prognosis remains with the clinician and is mainly based on the observation of clinical responsiveness. Despite their known shortcomings [54, 59], the current behavioral markers of responsiveness have major consequences on the commitment in resources, logistics, dedicated staff, and costs needed for the management of these patients or even dramatic in ethical controversies inviting media coverage and discussion in the public forum [72, 98, 99]. VS/UWS and MCS appear today neither static nor homogeneous, and a tacit revision of the current descriptive categories is de facto underway [60, 100]. A close scrutiny of the pathophysiology of responsiveness and its relevance in diagnosis/prognosis and in the definition of the boundaries between reactive VS/UWS and MCS is mandatory if scientific inquiry is to resolve the practical problem of determining a patient’s state of consciousness. In an effort to address this issue, the clinical and scientific communities have begun evaluating the potential usefulness of novel technologies to integrate and supplement standard clinical procedures and to investigate the mechanisms underlying the loss and recovery of consciousness [19, 43, 62, 83, 84, 90, 101–111].

Interest on consciousness is growing in neuroscience and medicine as well as in neurocomputing, artificial intelligence, and robotics with the rapid progress in the investigation of higher brain functions, advance in artificial intelligence, and diffuse perception of the inadequacy of traditional mind/body separations [8, 10, 112–114]. As a result, the concept of consciousness may vary depending on context, scientific approach, and background (from neurophysiological state of activation to self-awareness, to momentary interaction with the environment, etc.), and the definitions of consciousness and related terms remain to a significant extent inadequately characterized and ambiguous. The binary classification of consciousness vs. unconsciousness is being questioned on the ground of the neurophysiological correlates of preconscious processes [115–117], whereas the evidence for non-unitary models remains not definite [15]. The main epistemological issue about consciousness in humans and possibly in other species remains its definition beyond subjective feeling, verbal report, probabilistic inference (since by definition anyone’s own experience is inaccessible to others), and pragmatic principle of “revealed consciousness” [59, 60].

How consciousness arises in the brain remains fundamentally unsolved. It has been noted in his respect how research relies to a relevant extent on the linguistic neutrality of neurophysiological and pathophysiological “correlates” when the experimental paradigms and explanatory canons are not neutral about the mechanical relations with the brain and are supposed to investigate causes [118]. Neuroscience has advanced to the point that consciousness seems treatable as a scientific problem like others, disregarding objections that it may be epiphenomenal, not evolutionary in function, unaccountable by brain processes, intrinsically unsuitable to objective investigated, etc. [112]. Yet, a classification of DoC remains bound to the idea of responsiveness until a theory of consciousness inclusive of its quantitative characterization emerges from current scientific proposals. To this end, proper definitions for consciousness and responsiveness and an up-to-date scrutiny of the descriptors are needed in order to think scientifically about consciousness and start experimental studies.