Defining Consciousness: Lessons from Patients and Modern Techniques

W e would like to highlight the great interest recently raised in the scientific community by the increasing number of works on disorders of consciousness (DOC) confined to single subjects, or at most a few subjects. The purpose of this commentary is to expound on the possible role of case reports in exploring consciousness gradations ranging from a vegetative state (VS) and minimally-conscious state (MCS) to full consciousness. The peer-reviewed literature has not produced many case series or single case reports in this field, suggesting that speculations about DOC should be based upon empirical evidence, though isolated and incidental in nature. Thus analysis of the above case reports can teach important lessons about this extremely challenging group of patients, and pave the way for more systematic investigations.

To date, the research on these topics includes short reports of various kinds related to clinical, prognostic, and speculative issues. Some reports focused on the paradoxical awakening effect of several drugs that might favor emergence from unconscious states; a transient consciousness improvement has recently been described in a semi-comatose patient (Clauss et al., 2000) and in a minimally-conscious patient (Shames and Ring, 2008) after the use of the GABA_A agonist zolpidem, whereas the opposite findings were highlighted by others (Singh et al., 2008). In this same context, a stable improvement in the level of consciousness has been described in a few patients treated with intrathecal baclofen (Sarà et al., 2007; Taira and Hori, 2007) or amantadine (Schnakers et al., 2008). In this respect, we recently reported the awakening effect of intrathecal baclofen in five patients with persistent VS, who showed clinical improvements ranging from increased alertness to full recovery of consciousness. This observation, although confined only to a few subjects, enabled us to make some speculations about the paradoxical effect of intrathecal baclofen, and suggested two possible hypotheses for the mechanisms responsible for the reported improvements (Sarà et al., 2009). Although all these observations deserve further systematic investigation, these case series must be given credit for drawing attention to the apparent awakening effect of these drugs.

Other authors have recently written about the difficulty of the clinical and prognostic assessment of patients with DOC, in an effort to provide cases of misdiagnosis that support this difficulty. It remains challenging to decide whether a patient is in a VS or an MCS, or if the patient is instead suffering from a locked-in syndrome. As a result, VS is often overdiagnosed. An integrated approach that also includes neurophysiological and functional imaging paradigms has been suggested to confirm clinical impressions and avoid misdiagnosis. In this respect the usefulness of case-based lessons again arises; some case reports have raised questions about the reliability of neurophysiological findings in predicting outcomes in these patients (Pistoia et al., 2008; Jacome and Morilla-Pastor, 1990; Güttling et al., 1996). Others have highlighted the emergent usefulness of functional magnetic resonance imaging to provide reproducible and anatomically specific activation patterns in non-communicative patients during tasks involving external stimulation. The comparison of the patterns obtained in these patients with those of healthy subjects may not only provide data about the neural networks underlying normal consciousness, but may also yield practical suggestions about the prognosis of these patients. There are several experiences that have recently been described in individual patients. For example, two patients with MCS revealed language-related cortical activation with auditory stimulation using personalized narratives (Schiff et al., 2005); two patients in VS that subsequently emerged to MCS showed increased activity in the primary auditory cortex and in hierarchically higher-order associative temporal areas when their names were uttered by a familiar voice (Di et al., 2007); a patient in a VS demonstrated activation of the supplementary motor area when asked to imagine playing tennis, and the activation of regions associated with spatial navigation when asked to imagine moving around her house (Owen et al., 2007). The lessons to be gleaned from these case reports are difficult to pinpoint. They undoubtedly suggest that consciousness is not a phenomenon that can be localized, but that it is certainly active in vast cortical-subcortical networks, with all the ensuing theoretical and neurofunctional issues.

As stated above, case reports may be very useful in this emerging area of research, since they can contribute to more accurate assessment of patients with DOC, improve their management, and help to identify more reliable prognostic indicators for their recovery of consciousness.

Their contribution is all the more evident if the following aspects are taken into account. First, the considerable heterogeneity of patients with DOC makes the collection of large numbers of homogeneous and rigorous case histories extremely difficult from the point of view of inclusion criteria. Second, the chronic nature of persistent VS renders the collection of follow-up data on a large number of subjects difficult, with the obvious repercussion that an accurate estimate of the incidence of late improvement is lacking, probably because of erratic follow-up, incomplete reporting, or uncertain diagnoses. Hence the usefulness of well-designed case series that, even if confined to a few subjects, could guarantee homogeneity of criteria, could help avoid the possibility of using hypotheses that are actually false (type II error), and would enable more prolonged longitudinal observations to be made.

Although the above case reports may have some merit, ethical and scientific prudence prevents one from drawing conclusions exclusively based on the data provided. Indeed, well-documented case reports may prompt reflections on many issues concerning DOC, but more robust data can only be gathered by conducting more rigorous studies. This is made more difficult by prognostic issues, which by their very nature raise ethical and legal dilemmas with respect to the considerations of the withdrawal of life-sustaining treatments.

Further, within the framework of case reports and case series a clear-cut distinction is called for between simple descriptive case reports and case studies based on a single-subject research design. This distinction is fundamental because whereas the former are basically narrative in essence (Shames and Ring, 2008; Sarà et al., 2007; Taira and Hori, 2007; Pistoia et al., 2008), the latter are based on the formulation of a hypothesis that, through a precise methodology applied to several individual cases, is then confirmed or disproved (Schnakers et al., 2008; Sarà et al., 2009; Di et al., 2007; Owen et al., 2007). What led to the development of such case-report-based knowledge covering various aspects of the disorders of consciousness?

This issue can be thoroughly examined by considering the most famous case report described in the history of neurological science: the Phineas Gage experience (Damasio, 1994). He was a railroad worker, who as a consequence of a traumatic brain injury that only involved his frontal lobes, reported severe effects on his personality and social functioning. From that point on, the prefrontal cortex has been regarded as the “organ of civilisation,” and a large number of similar behavioral alterations have been recognized in patients with traumatic injuries to the prefrontal region, or treated by means of brain surgery for brain tumors and psychiatric or epileptic disorders (García -Molina, 2008). As a result, Phineas Gage's case contributed much to the evolution of the science of localizing brain functions.

Basically, there are three main elements that enable a case report to foster the emergence of fresh research: (1) it has a fortuitous and unpredictable course with improbable and confounding outcomes, (2) it occurs at a crucial historical and epistemological moment characterized by increasing doubts about an important issue, and (3) it goes beyond the standard guidelines in terms of diagnosis and therapy.

With vegetative and minimally-conscious patients, these main elements arise again: the fact that the essence of consciousness is currently unknown, and the fact that we cannot localize it within specific cerebral areas, results in the realization that what we learn about it is derived from fortuitous and irreproducible observations. Moreover, the condition of patients with DOC is a direct result of the period in which they live, although improvements seen by patients after treatment of the acute stage of their pathology, which in recent years have increased their survival rates, have not resulted in a clearer understanding of consciousness itself. Finally, patients often show unexpected responses to treatments administered for other indications, thus defying what was established by existing guidelines.

All of these features contribute to the intriguing nature of case reports addressing consciousness, and are a considerable component of their scientific interest; however, case reports can only be considered scientifically worthy if authors formulate specific hypotheses about the clinical events they observe. These hypotheses may lay the groundwork for subsequent more systematic investigations based on larger samples and more rigorous methodologies, thus contributing to our current knowledge about consciousness and its impairment and recovery.

Moreover, compared to Phineas Gage, patients with DOC are even more complicated because they are completely different from one another with respect to the nature and location of their brain lesions. Consequently they are not comparable, and each should be considered on an individual basis. This heterogeneity prompts reflections on the requirements of future research on consciousness.

In the case of Phineas Gage, a single fortuitous experience suggested the role of the prefrontal cortex in moral and social cognition. Thereafter modern scientific literature confirmed this pioneering observation by recognizing similar behavioral disorders in a large number of patients with the same lesion. In this respect, the science of the localization of brain functions was the result of knowledge that utilized experience drawn from a large number of comparable subjects.

A case-report-based approach will not work exactly in the same way to help unravel the mysteries of consciousness. Indeed, the striking heterogeneity of patients with DOC makes the systematic verification of intuitions arising from individual subjects difficult, and is an indirect sign of the delocalized nature of consciousness itself.

In fact, the absence of specific types of brain damage being associated with DOC suggests that consciousness is not localized within discrete brain areas, and this is why the assignment of specific regions to any hypothetical domain of consciousness remains unresolved. Compared to simple cognitive abilities, consciousness is less likely to be localized to specific brain structures, since it requires the synergy of several interconnected neural networks whose identification is not possible using standard scientific techniques. All this suggests that consciousness does not spring from a single specialized area of the brain, and it should instead be addressed by investigating how different brain regions communicate with each other and their functional connectivity. This is also in accord with a recent study suggesting that the VS is the result of a reduction in global interconnectivity, rather than dysfunction of a single area (Laureys, 2005).

In this respect, a case-report-based analysis of consciousness, although partially invalidated by the heterogeneity of patients' anatomical and pathological features, might pave the way for additional studies that could aid our understanding of consciousness, and may be the most practical way to pursue the study of DOC.

In conclusion, individual case reports can teach us important lessons about patients with DOC, because as in the case of Phineas Gage, they may reveal secrets that will be useful in formulating future treatments for DOC.