The emerging studies uncovering occult conscious awareness in patients with DoC can be grouped into two general categories: functional neuroimaging (particularly fMRI and FDG-PET) and recording of brain electrical potentials. The functional neuroimaging studies have been more dramatic, provocative, and convincing, but the brain electrical potential recording studies have the advantage of being available more widely.

Owen and colleagues first showed that fMRI could reliably reveal evidence of conscious awareness in one patient in a vegetative state (VS) even when a careful neurological examination could not [13]. The publication of subsequent case reports and small series of VS patients confirmed and expanded his original findings [14–17]. The experimental paradigm had a unique feature compared to those used in earlier studies. Unlike previous passive fMRI paradigms, they instructed the patient to imagine performing a particular motor activity, such as playing tennis or walking through the house. Patients so instructed who retained the capacity to perform the ideational task showed focal regions of evoked increases in blood-oxygen-level-dependent (BOLD) fMRI signal representing increased blood flow in brain premotor areas. They termed the fMRI responses resulting from this ideational task “willful modulation of brain activity” [16]. The subset of patients who retain this capacity of “top-down cognitive functioning” have been shown to possess greater connectivity between the anterior thalamus and prefrontal cortex [18].

Although most investigators have accepted that the fMRI findings of willful modulation of brain activity indicated the presence of at least some degree of conscious awareness, some knowledgeable critics have expressed skepticism about the quality or extent of the patients’ awareness that these findings represented [19, 20] or questioned whether the investigators had “conflated findings associated with willful consciousness with the actual occurrence of willful consciousness” [21]. Other skeptics, with experience performing fMRI studies in DoC, have emphasized the formidable technical hurdles that must be overcome for researchers to obtain consistent and reliable fMRI data on which to draw firm conclusions, because of inter-examination interval variations in patient arousal state, motion, medication effects, and other variables affecting signal acquisition and analysis [14, 22]. To establish consistent and reliable data, repeated fMRI examinations are just as necessary as are repeated clinical examinations to validly assess the presence or absence of conscious awareness [3].

Several investigators have made the analogous claim of the technical capacity to detect covert awareness in patients with DoC using sophisticated EEG [23, 24], preserved EEG organization [25], or evoked potential recordings [26, 27] as well as the capacity to use bispectral analysis recordings of brain electrical potentials on normal people during general anesthesia for the same purpose [28]. Some of these reports have been controversial. For example, following the publicized report by Cruse and colleagues [29] of a bedside EEG device that could detect awareness in some VS patients, Goldfine and colleagues [30] reanalyzed the investigators’ data and concluded that the published findings were invalid, a claim that was rebutted by the investigators.

The most direct effect of the emerging fMRI reports showing the presence of awareness in a few patients with the clinical diagnosis of VS is that it changes the diagnosis in those patients because evidence for awareness must be totally absent for a diagnosis of VS. The accepted diagnostic criteria for VS are clinical and are delineated mostly in the negative, i.e., stipulating those activities that VS patients cannot perform [31]. Delineating diagnostic criteria by negative capacities encourages false-positive diagnostic errors because reasons other than the brain damage may account for why patients cannot perform certain tasks. For example, unconscious patients may be tested improperly without using validated assessment scales, they may be sedated by medications treating seizures and other conditions, or they may have medical comorbidities such as infection or dehydration that produce a toxic encephalopathy suppressing responsiveness [32]. These factors and the nature of the negative delineation of the diagnostic criteria for VS help explain why false-positive diagnostic errors have been reported in 40 % of patients in VS [33].

If we accept that the fMRI data showing willful modulation of brain activity are valid in certain cases of VS, then the original diagnosis must be altered because evidence of awareness invalidates the diagnosis of VS. Prior to these reports, neurologists believed that a careful neurological examination using an optimal clinical assessment scale for detecting conscious awareness – such as the Coma Recovery Scale-Revised (CRS-R) [34] – constituted the gold standard for diagnosis. Now it appears that a small subset of patients diagnosed as VS according to accepted clinical criteria have been misdiagnosed and should be correctly categorized as a minimally conscious state (MCS) rather than VS [35].

The false-positive diagnoses of VS raise the larger question of whether the clinical diagnostic criteria for VS should be revised to incorporate functional neuroimaging data and for fMRI or FDG-PET to become a routine part of clinical assessment of these patients, as Coleman and colleagues [36] have advocated. I agree with them that over the next several years, the diagnostic criteria of VS should evolve from being purely clinical to clinical plus functional neuroimaging. But before this can occur, more systematic studies must be conducted to better delineate and standardize the fMRI and FDG-PET findings. Clinical syndromes such as VS and MCS have been carved out of the continuum of diffuse brain damage. The precise boundaries of these syndromes will likely need adjustment as the functional neuroimaging and other studies provide greater insights into the anatomy of consciousness and the pathophysiology of DoC.

In the largest study of functional neuroimaging in DoC, Stender et al. [37] showed that FDG-PET patterns had a higher sensitivity for detecting awareness among MCS patients (93 %) than fMRI (45 %) and also a higher congruence with the findings of awareness on clinical examination using the CRS-R (85 % vs. 63 %). They found that 32 % of their clinically unresponsive patients had either fMRI or FDG-PET evidence for at least minimal awareness. They recommended that a complete evaluation for occult awareness in DoC patients should include both of these functional neuroimaging modalities and the CRS-R [37].

Whether patients in VS or MCS will later improve or are destined to remain in that state chronically is an essential determination for clinicians. The Multi-Society Task Force on PVS [31] concluded that once a patient had been in VS from a non-traumatic etiology for more than 3 months or from traumatic brain injury (TBI) for more than a year, there was only a slight change for significant improvement subsequently. More recent data have shown these predictions to be overly pessimistic, particularly in the TBI subgroup. Several reports have described rare but more frequent late spontaneous improvements in the level of consciousness of some VS patients [38–41].

Beginning with the initial report of Owen et al. [13], several investigators have reported that the small subset of VS patients showing fMRI patterns of willful modulation of brain activity also were those who later were most likely to show spontaneous clinical improvement. Owen’s initial patient, who was clinically in VS at 5 months after TBI and who showed fMRI evidence of awareness by willful modulation, improved spontaneously to show clinical signs of awareness at 11 months after injury. Other investigators have made similar observations about a few patients in the subset of VS patients who demonstrated willful modulation [18] or who showed characteristic fMRI responses to hearing the subject’s own name spoken [42]. In the large recent study of functional neuroimaging in DoC patients, FDG-PET correctly predicted outcome in 74 %, while fMRI prediction was correct in 56 % [37].

It has been known for decades that the outcomes of patients in VS resulting from TBI were more favorable than patients in VS resulting from hypoxic-ischemic neuronal damage. Most of the VS patients who have been reported to demonstrate willful modulation and who later spontaneously improved were in VS as a result of TBI and not hypoxic-ischemic neuronal injury. Similarly, studies measuring EEG responses of MCS patients to ideational tasks show positive activation in most patients who had TBI but in none who had hypoxic-ischemic injuries [23]. Yet, some studies also have shown activation responses in hypoxic-ischemic cases. Monti and colleagues [16] found that six of ten DoC patients who were able to respond to an executive function task were from non-traumatic brain injury, including two of three VS patients who had suffered hypoxic-ischemic injury. Similarly, John and colleagues [43] reported one post-cardiac arrest hypoxic-ischemic VS patient in whom QEEG showed the ability to perform a mental imagery task. These small numbers show that although DoC patients with hypoxic-ischemic brain injuries may be among those detected to have occult awareness, they remain the minority of reported cases.

Many TBI patients develop VS as a result of diffuse axonal injury (DAI), a serious condition in which rotational traumatic forces shear axons diffusely at the junction between the cerebral gray matter and white matter. Although DAI often causes a severe brain injury with a poor outcome, because neurons usually remain intact, it is generally not as irreversible as a hypoxic-ischemic neuronal injury [44, 45]. The most dramatic example is the unprecedented recovery of a patient in MCS for 19 years before he began speaking and interacting in whom diffusion tensor imaging showed findings interpreted as axonal regrowth in the posterior parietal white matter [46]. Both FDG-PET and fMRI findings may have prognostic value among TBI patients (and in some hypoxic-ischemic patients) who demonstrate willful modulation because they may serve as a marker for subsequent spontaneous clinical improvement.

Once otherwise unresponsive patients with willful modulation of brain activity could be identified, investigators made attempts to establish systems to allow the patients to communicate by using their fMRI responses. One of the patients described by Monti and colleagues [16] was taught to reliably respond “yes” or “no” to binary questions by assigning the tennis-playing ideational paradigm to indicate “yes” and the room-walking ideational paradigm to indicate “no.” The inability of an aware patient to communicate (particularly one wrongly believed to be unconscious) obviously produces profound suffering. Establishing a reliable method for the patient to communicate is essential to mitigate their suffering, to acknowledge that the medical and nursing staff knows they are aware, and to allow patients to express themselves, to optimize neurorehabilitation and palliative care, and possibly to participate in medical decision-making.

Investigators have tested MCS patients who remain aware but profoundly unresponsive to test various strategies of communication. Recognition of the patient’s own name was found to be the most reliable test, yielding 100 % accuracy in the absence of a coexisting confusional state in a study of 144 patients in MCS after TBI [47]. Using fMRI responses, Naci and Owen [48], using a convenience sample of three DoC patients, found that one VS patient and one of two MCS patients could successfully use selective auditory attention to convey their ability to follow commands and to communicate.

Despite these encouraging findings, there remain serious barriers to using fMRI-evoked changes in response to ideational paradigms as responses for communication, particularly in obtaining consistent and reliable responses. Very few of the patients showing willful modulation have been able to achieve successful communication systems. Patients with VS and MCS, especially those from TBI, often also have aphasia, sedation from anticonvulsant drugs, global cognitive impairment from diffuse brain damage, and confusion from medical comorbidities. Each of these factors diminishes reliable responsiveness that makes communication difficult or impossible. Yet, because establishing communication is such an important goal, each patient showing willful modulation should be screened for candidacy for communication.

The process of medical decision-making in patients with DoC has been the subject of much discussion [35, 49, 50]. Most often, the question has been framed as whether patients in irreversible VS should continue to receive life-sustaining therapy including hydration and nutrition by medical means or if they should be allowed to die by discontinuing these therapies [51–54]. This physician-centered locus of medical decision-making for patients with DoC is archaic and inappropriate because it wrongfully substitutes the values and preferences of the physician for those of the patient, thereby disenfranchising patients from their human right of self-determination.

It has been observed in this context that the appropriate locus of medical decision-making should be patient centered, i.e., the correct decision is that which follows and respects the patient’s wishes and preferences [55]. They pointed out that “patient centeredness [is] an end in itself and a legitimate aspect of health care quality that must be measured and improved.” Thus, physicians must devote effort to divine the wishes of the patient whose values and preferences should guide medical decision-making for their own treatment. The patient’s preferences can be sought in prior executed advance directives for medical care and past statements made by the patient to relatives, friends, and physicians. The lawful surrogate decision-maker is authorized to make medical decisions for the patient in collaboration with the attending physician of record in a process of shared decision-making following their best understanding of the patient’s wishes [56].

The very few VS or MCS patients who demonstrate willful modulation of brain activity by fMRI and have successfully achieved yes-no communication systems raise the question of the extent to which this capacity qualifies them to actively participate in their own medical decision-making. The closest analogy to this novel circumstance is the patient in a locked-in syndrome who retains normal cognition and awareness but is so profoundly paralyzed as to be incapable of communicating except for yes-no responses using a retained rudimentary voluntary movement, such as blinking or moving the eyes vertically. There has been much work accomplished to establish effective communication systems for locked-in patients using computers, lasers, and other technologies [57].

The essential question is whether the reliability of a binary yes-no response by fMRI achieves the threshold to validate a patient’s consent or refusal of therapy. In ordinary clinical circumstances, physicians conduct discussions with patients or surrogates, explaining treatments and outcomes and answering questions in a consent process leading to their understanding and ability to reach a treatment decision. Most neurologists have concluded that because DoC patients demonstrating willful modulation, like those in a locked-in syndrome, can communicate only with rudimentary yes-no fMRI responses that categorically lack nuance and cannot convey understanding, these responses are too crude to achieve the criteria for a valid decision to continue or stop life-sustaining therapy. Therefore, surrogate decision-making is essential to make the patient’s consent or refusal valid.

Medical treatment decisions for patients with DoC extend far beyond the vexing question of continuing life-sustaining medically supplied hydration and nutrition. Three classes of treatment have been impacted by innovations in functional neuroimaging: novel stimulatory protocols to attempt to improve responsiveness, neurorehabilitation, and palliative care.

Neurologists and physiatrists have attempted to stimulate patients in VS and MCS to try to improve their level of responsiveness using medications, environmental and physical stimuli, and more recently, electrical brain stimulation. A Cochrane systematic review of stimulation treatments in VS patients concluded that they are unsuccessful [58]. Amantadine is the exception: in a controlled trial, it was shown to improve the responsiveness of TBI patients with VS and MCS [59]. Patients in MCS are much more responsive to medications and other stimulation treatments; several treatments have shown benefit in improving their function [10]. Physicians should consider prescribing sequential trials of amantadine, levodopa, zolpidem [60], and other medications to stimulate patients with MCS in an attempt to improve their responsiveness [8].