Marco Sarà

Previous evidence suggests that hallucinations and delusions may be detected in patients with the most severe forms of motor disability including locked-in syndrome (LIS). However, such phenomena are rarely described in LIS and their presence may be underestimated as a result of the severe communication impairment experienced by the patients. In this study, we retrospectively reviewed the clinical history and the neuroimaging data of a cohort of patients with LIS in order to recognize the presence of hallucinations and delusions and to correlate it with the pontine damage and the presence of any cortical volumetric changes. Ten patients with LIS were included (5 men and 5 women, mean age 50.1 ± 14.6). According to the presence of indicators of symptoms, these patients were categorized as hallucinators (n = 5) or non-hallucinators (n = 5). MRI images of patients were analyzed using Freesurfer 6.0 software to evaluate volume differences between the two groups. Hallucinators showed a selective cortical volume loss involving the fusiform (p = 0.001) and the parahippocampal (p = 0.0008) gyrus and the orbital part of the inferior frontal gyrus (p = 0.001) in the right hemisphere together with the lingual (p = 0.01) and the fusiform gyrus (p = 0.01) in the left hemisphere. Moreover, a volumetric decrease of bilateral anterior portions of the precuneus was recognized in the hallucinators (right p = 0.01; left p = 0.001) as compared to non-hallucinators. We suggested that the presence of hallucinations and delusions in some LIS patients could be accounted for by the combination of a damage of the corticopontocerebellar pathways with cortical changes following the primary brainstem injury. The above areas are embedded within cortico-cortical and cortico-subcortical loops involved in self-monitoring and have been related to the presence of hallucinations in other diseases. The two main limitations of our study are the small sample of included patients and the lack of a control group of healthy individuals. Further studies would be of help to expand this field of research in order to integrate existing theories about the mechanisms underlying the generation of hallucinations and delusions in neurological patients.

The experience of pain in disorders of consciousness is still debated. Neuroimaging studies, using functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET), multichannel electroencephalography (EEG) and laser-evoked potentials, suggest that the perception of pain increases with the level of consciousness. Brain activation in response to noxious stimuli has been observed in patients with unresponsive wakefulness syndrome (UWS), which is also referred to as a vegetative state (VS), as well as those in a minimally conscious state (MCS). However, all of these techniques suggest that pain-related brain activation patterns of patients in MCS more closely resemble those of healthy subjects. This is further supported by fMRI findings showing a much greater functional connectivity within the structures of the so-called pain matrix in MCS as compared to UWS/VS patients. Nonetheless, when interpreting the results, a distinction is necessary between autonomic responses to potentially harmful stimuli and conscious experience of the unpleasantness of pain. Even more so if we consider that the degree of residual functioning and cortical connectivity necessary for the somatosensory, affective and cognitive-evaluative components of pain processing are not yet clear. Although procedurally challenging, the particular value of the aforementioned techniques in the assessment of pain in disorders of consciousness has been clearly demonstrated. The study of pain-related brain activation and functioning can contribute to a better understanding of the networks underlying pain perception while addressing clinical and ethical questions concerning patient care. Further development of technology and methods should aim to increase the availability of neuroimaging, objective assessment of functional connectivity and analysis at the level of individual cases as well as group comparisons. This will enable neuroimaging to truly become a clinical tool to reliably investigate pain in severely brain-injured patients as well as an asset for research.

To reveal covert abilities in a minimally conscious state (MCS) through an innovative activation paradigm based on olfactory imagery. Case study. A patient in MCS was asked to 'imagine an unpleasant odour' or to 'relax' in response to the appearance on a screen of a downward pointing arrow or a cross, respectively. Electrophysiological responses to stimuli were investigated by means of an 8-channel EEG equipment and analysed using a specific threshold algorithm. The protocol was repeated for 10 sessions separated from each other by 2 weeks. Accuracy, defined as the number of successes with respect to the total number of trials, was used to evaluate the number of times in which the classification strategy was successful. Analyses of accuracy showed that the patient was able to activate and to relax himself purposefully and that he optimized his performances with the number of sessions, probably as a result of training-related improvements. Subtle signs of consciousness may be under-estimated and need to be revealed through specific activation tasks. This paradigm may be useful to detect covert signs of consciousness, especially when patients are precluded from carrying out more complex cognitive tasks.

The neurobiological approach to consciousness moves from the assumption that all phenomenal experiences are based on neuronal activity in the brain. Consciousness has two main components: wakefulness and awareness. While it may be relatively easy to determine the neuronal correlates of wakefulness, it is not the same for awareness, of which the neural correlates are poorly understood. Knowledge of the circuitry and the neurochemistry of the sleep/wake condition is necessary but not sufficient to understand the circuitry and neurochemistry of consciousness. Disorders of consciousness (DOCs) include coma, vegetative state and minimally conscious state. The study of DOCs and of the electrophysiological changes underlying general anaesthesia-induced loss of consciousness may help in understanding the neuronal correlates of consciousness. In turn, the understanding of the neural bases of consciousness may help in designing interventions aimed at restoring consciousness in DOC patients. Sporadic cases of recovery from a DOC have been reported after the administration of various pharmacological agents (baclofen, zolpidem, amantadine etc.). This review provides an overview of such drugs, which are from various and diverging classes but can be grouped into two main categories: CNS stimulants and CNS depressants. The available data seem to suggest an awakening effect obtained with CNS depressants rather than stimulants, the latter being more effective at improving functional cognitive and behavioral recovery in patients who have spontaneously regained an appreciable level of consciousness. There is a need for more rigorous systematic trials and further investigation of the above treatments, with particular attention paid to their mechanisms of action and the neurotransmitters involved.

In this paper, we review the contribution of our research group to the study of human consciousness by quantitative electroencephalographic (EEG) techniques. We posit that EEG techniques can be extremely useful for a direct measurement of brain electrophysiological activity related to human consciousness for their unsurpassable high temporal resolution (milliseconds). This activity can be expressed in terms of event-related potentials as well as changes of EEG rhythms of interest, for example the dominant alpha rhythms (about 8-12 Hz). The results of our studies, and those of several independent groups, lead support to the hypothesis that these techniques provide important insights about the neurophysiologic mechanisms underlying cortical neural synchronization/desynchronization and the regulation of neuromodulatory systems (e.g. dopaminergic, noradrenergic, cholinergic, etc.) at the basis of brain arousal and consciousness in healthy subjects and in patients with impairment of the consciousness. A possible interaction of these mechanisms and the drugs administered to patients with consciousness disorders is discussed.

Cases of recovery from vegetative and minimally conscious state after the administration of various pharmacological agents have been recently reported. These agents include CNS depressants (zolpidem, baclofen, lamotrigine) and CNS stimulants (tricyclic antidepressants, selective serotonin reuptake inhibitors, dopaminergic agents, methylphenidate). The action of CNS depressants as awakening agents sounds paradoxical, as they are commonly prescribed to slow down brain activity in the management of anxiety, muscle tension, pain, insomnia and seizures. How these drugs may improve the level of consciousness in some brain-injured patients is the subject of intense debate. Here we hypothesize that CNS depressants may promote consciousness recovery by reversing a condition of GABA impairment in the injured brain, restoring the normal ratio between synaptic excitation and inhibition, which is the prerequisite for any transition from a resting state to goal-oriented activities (GABA impairment hypothesis). Alternative or complementary mechanisms underlying the improvement of consciousness may include the reversal of a neurodormant state within areas affected by diaschisis (diaschisis hypothesis) and the modulation of an informative overload to the cortex as a consequence of filter failure in the injured brain (informative overload hypothesis). A better understanding of how single agents act on neural networks, whose functioning is critical for recovery, may help to advance a tailored pharmacological approach in the treatment of severely brain injured patients.

The mass media have recently pointed out the likelihood of diagnostic errors in post-coma patients. Late recoveries of consciousness, even after 20 years, might indicate hidden misdiagnoses that are not corrected over a long period of time. The rate of misdiagnoses of patients in a vegetative state is very high when based on behavioral assessment strategies alone. An extremely restrictive motor repertoire, as occurs in locked-in patients, seems to be the major factor responsible for diagnostic confusion. Functional neuroimaging techniques are regarded as promising tools in unearthing covert awareness in behaviorally unresponsive patients who are unable to produce any motor output. However, unless we believe that these patients persistently live in an unconvincing Cartesian-like state , in which thinking and acting are mutually dissociated, we have to admit that a new taxonomy for low responsive states is called for. This taxonomy should take into account the possible syndromic overlap between disorders of consciousness and locked-in syndrome. We should suspect a “locked-in state” in behaviorally unresponsive patients unless we reach strong evidence that such is not the case; this is the only way to avoid dramatic misdiagnoses.

Background. Establishing prognosis in patients in a persistent vegetative state (VS) is still challenging. Neural networks underlying consciousness may be regarded as complex systems whose outputs show a degree of unpredictability experimentally quantifiable by means of nonlinear parameters such as approximate entropy (ApEn). Objective. The authors propose that the VS might be the result of derangement of the above neural networks, with an ensuing decrease in complexity and mutual interconnectivity: this might lead to a functional isolation within the cerebral cortex and to a reduction in the chaotic behavior of its outputs, with monotony taking the place of unpredictability. To test this hypothesis, the authors investigated whether nonlinear dynamics methods applied to electroencephalography (EEG) recordings may be able to predict outcomes. Methods. A total of 38 vegetative patients and 40 matched healthy controls were investigated. At admission, all patients were assessed by means of the Extended Glasgow Outcomes Coma Scale (E-GOS) and the Coma Recovery Scale–Revised (CRS-R). At the same time an EEG recording was performed and used for time series analysis and ApEn computation. Patients were clinically reassessed at 6 months from the first evaluation. Results. Mean ApEn values (0.73, standard deviation [SD] = 0.12 vs 0.97, SD = 0.02; P < .001) were lower in patients than in controls. Patients with the lowest ApEn values either died (n = 14) or remained in a VS (n = 12), whereas patients with the highest ApEn values became minimally conscious (n = 5) or showed partial (n = 4) or full recovery (n = 3). Conclusions. These findings suggest that dynamic correlates of neural residual complexity might help in predicting outcomes in vegetative patients.