The Comorbidities Coma Scale (CoCoS): Psychometric Properties and Clinical Usefulness in Patients With Disorders of Consciousness.

Although comorbidities have a well-known impact on the functional recovery of patients with disorders of consciousness, including coma, vegetative state (VS), and minimally conscious state (MCS), a specific tool for their assessment in this challenging group of patients is lacking. For this aim, a multistep process was used to develop and validate the Comorbidities Coma Scale (CoCoS) in a sample of 162 patients with a diagnosis of coma, VS or MCS admitted to four Acute Inpatient Rehabilitation Units. To establish the psychometric properties of the scale, content validity, and internal consistency were investigated through Exploratory Factor Analysis in the whole sample (n = 162). Interrater reliability, assessed by the weighted Cohen's kappa (Kw), and concurrent validity of the scale as compared to the Greenfield Scale, assessed by ρ Spearman's correlation coefficient, were investigated in a subsample of patients (n = 52) within two of the above units. Our findings provided evidence of a good content validity of the scale, with the identification of a 12-factor structure representing the different comorbid dimensions of the target population. Inter-rater reliability was excellent in both the rehabilitation units where the assessment was made [Kw 0.98 (95% CI 0.96-0.99)]. CoCoS total scores correlated significantly with total scores of the Greenfield Scale (ρ = 0.932, 95% CI 0.89-0.96; P < 0.0001) indicating that CoCoS has concurrent validity while being more informative about the specific pattern of comorbidities of these challenging patients. The CoCos is a new tool which standardizes the approach to assessment of comorbid conditions and reliably identifies the category and severity of each comorbidity detected. It may be used for both clinical and research applications.

Cognitive and Emotional Empathy in Individuals with Spinal Cord Injury.

BACKGROUND: Empathy has been conceptualized as comprising a cognitive and an emotional component, the latter being further divided into direct and indirect aspects, which refer, respectively, to the explicit evaluation of the observer's feelings while attending someone in an emotional situation and to the physiological response of the observer. Empathy has been previously investigated in several neurological disorders. OBJECTIVE: This study is aimed at investigating empathy in patients with spinal cord injury (SCI). We hypothesize that, due to deafferentation following their injury, SCI patients will display difficulty in the processing of emotional stimuli and blunted empathic responses as compared to healthy controls. MATERIALS AND METHODS: 20 patients with spinal cord injury (SCI) (12 males and 8 females, mean age = 50.9, standard deviation (SD) = 16.1 years; mean education = 10.9, SD = 4.1 years) were included in the study and compared to 20 matched healthy subjects. Participants were investigated using the State-Trait Anxiety Inventory (Form Y) (STAI-Y), the Beck Depression Scale, and the Toronto Alexithymia Scale. Moreover, participants were further evaluated by means of the Interpersonal Reactivity Index (IRI), which explores both cognitive and emotional aspects of empathy, and through an experimental protocol based on the use of a modified version of the computerized Multifaceted Empathy Test (MET) to evaluate emotional (direct and indirect) empathy and the ability to judge the valence of complex emotional scenes. RESULTS: As compared to healthy controls, SCI patients reported higher scores on the Perspective-Taking subscale of the IRI, while, on the modified MET, they were less accurate in identifying the valence of neutral scenes, notwithstanding their spared direct and indirect emotional empathy ability. Furthermore, we found a significant negative correlation between the time interval since injury and the direct emotional empathy scores on the positive images, as well as a negative correlation with the indirect emotional empathy scores on both positive and neutral images, indicating a blunting of the empathic responses as time elapses. CONCLUSION: Results suggest that SCI patients, when analyzing the meaning of emotional stimuli, tend to rely on a cognitive empathy strategy rather than on emotion simulation.

Cortical Brain Changes in Patients With Locked-In Syndrome Experiencing Hallucinations and Delusions.

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.

Development of the Italian Version of the Near-Death Experience Scale.

Near-death experiences (NDEs) have been defined as any conscious perceptual experience occurring in individuals pronounced clinically dead or who came very close to physical death. They are frequently reported by patients surviving a critical injury and, intriguingly, they show common features across different populations. The tool traditionally used to assess NDEs is the NDE Scale, which is available in the original English version. The aim of this study was to develop the Italian version of the NDE Scale and to assess its reliability in a specific clinical setting. A process of translation of the original scale was performed in different stages in order to obtain a fully comprehensible and accurate Italian translation. Later, the scale was administered to a convenience sample of patients who had experienced a condition of coma and were, at the time of assessment, fully conscious and able to provide information as requested by the scale. Inter-rater and test-retest reliability, assessed by the weighted Cohen's kappa (Kw), were estimated. A convenience sample of 20 subjects [mean age ± standard deviation (SD) 51.6 ± 17.1, median time from injury 3.5 months, interquartile range (IQR) 2-10] was included in the study. Inter-rater [Kw 0.77 (95% CI 0.67-0.87)] and test-retest reliability [Kw 0.96 (95% CI 0.91-1.00)] showed good to excellent values for the total scores of the Italian NDE Scale and for subanalyses of each single cluster of the scale. An Italian Version of the NDE Scale is now available to investigate the frequency of NDE, the causes for NDE heterogeneity across different life-threatening conditions, and the possible neural mechanisms underlying NDE phenomenology.

Disorders of Consciousness: Painless or Painful Conditions?-Evidence from Neuroimaging Studies.

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.

Disembodied Mind: Cortical Changes Following Brainstem Injury in Patients with Locked-in Syndrome.

Locked-in syndrome (LIS) following ventral brainstem damage is the most severe form of motor disability. Patients are completely entrapped in an unresponsive body despite consciousness is preserved. Although the main feature of LIS is this extreme motor impairment, minor non-motor dysfunctions such as motor imagery defects and impaired emotional recognition have been reported suggesting an alteration of embodied cognition, defined as the effects that the body and its performances may have on cognitive domains. We investigated the presence of structural cortical changes in LIS, which may account for the reported cognitive dysfunctions. For this aim, magnetic resonance imaging scans were acquired in 11 patients with LIS (6 males and 5 females; mean age: 52.3±5.2SD years; mean time interval from injury to evaluation: 9±1.2SD months) and 44 healthy control subjects matching patients for age, sex and education. Freesurfer software was used to process data and to estimate cortical volumes in LIS patients as compared to healthy subjects. Results showed a selective cortical volume loss in patients involving the superior frontal gyrus, the pars opercularis and the insular cortex in the left hemisphere, and the superior and medium frontal gyrus, the pars opercularis, the insular cortex, and the superior parietal lobule in the right hemisphere. As these structures are typically associated with the mirror neuron system, which represents the neural substrate for embodied simulation processes, our results provide neuroanatomical support for potential disembodiment in LIS.

EEG-detected olfactory imagery to reveal covert consciousness in minimally conscious state.

PRIMARY OBJECTIVE: To reveal covert abilities in a minimally conscious state (MCS) through an innovative activation paradigm based on olfactory imagery. RESEARCH DESIGN: Case study. METHODS AND PROCEDURES: 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. MAIN OUTCOMES AND RESULTS: 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. CONCLUSIONS: 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.

Contribution of Interoceptive Information to Emotional Processing: Evidence from Individuals with Spinal Cord Injury.

There is much evidence to suggest that recognizing and sharing emotions with others require a first-hand experience of those emotions in our own body which, in turn, depends on the adequate perception of our own internal state (interoception) through preserved sensory pathways. Here we explored the contribution of interoception to first-hand emotional experiences and to the recognition of others' emotions. For this aim, 10 individuals with sensory deafferentation as a consequence of high spinal cord injury (SCI; five males and five females; mean age, 48 ± 14.8 years) and 20 healthy subjects matched for age, sex, and education were included in the study. Recognition of facial expressions and judgment of emotionally evocative scenes were investigated in both groups using the Ekman and Friesen set of Pictures of Facial Affect and the International Affective Picture System. A two-way mixed analysis of variance and post hoc comparisons were used to test differences among emotions and groups. Compared with healthy subjects, individuals with SCI, when asked to judge emotionally evocative scenes, had difficulties in judging their own emotional response to complex scenes eliciting fear and anger, while they were able to recognize the same emotions when conveyed by facial expressions. Our findings endorse a simulative view of emotional processing according to which the proper perception of our own internal state (interoception), through preserved sensory pathways, is crucial for first-hand experiences of the more primordial emotions, such as fear and anger.

Intrathecal baclofen: effects on spasticity, pain, and consciousness in disorders of consciousness and locked-in syndrome.

Disorders of consciousness (DOCs) include coma, vegetative state (VS), and minimally conscious state (MCS). Coma is characterized by impaired wakefulness and consciousness, while VS and MCS are defined by lacking or discontinuous consciousness despite recovered wakefulness. Conversely, locked-in syndrome (LIS) is characterized by quadriplegia and lower cranial nerve paralysis with preserved consciousness. Intrathecal baclofen (ITB) is a useful treatment to improve spasticity both in patients with DOCs and LIS. Moreover, it supports the recovery of consciousness in some patients with VS or MCS. The precise mechanism underlying this recovery has not yet been elucidated. It has been hypothesized that ITB may act by reducing the overload of dysfunctional sensory stimuli reaching the injured brain or by stabilizing the imbalanced circadian rhythms. Although the current indication of ITB is the management of severe spasticity, its potential use in speeding the recovery of consciousness merits further investigation.

Comorbidities: a key issue in patients with disorders of consciousness.

The aim of this study was to identify the impact of comorbidities on outcomes of patients with vegetative state (VS) or minimally conscious state (MCS). All patients in VS or MCS consecutively admitted to two postacute care units within a 1-year period were evaluated at baseline and at 6 months through the Coma Recovery Scale-Revised Version and the Disability Rating Scale (DRS). Comorbidities were also recorded for each patient along the same period. Six-month outcomes included death, full recovery of consciousness, and functional improvement. One hundred and thirty-nine patients (88 male and 51 female; median age, 59 years) were included. Ninety-seven patients were in VS (70%) and 42 in MCS (30%). At 6 months, 33 patients were dead (24%), 39 had a full recovery of consciousness (28%), and 67 remained in VS or MCS (48%). According to DRS scores, 40% of patients (n=55) showed a functional improvement in the level of disability. One hundred and thirty patients (94%) showed at least one comorbidity. Severity of comorbidities (hazard ratio [HR]=2.8; 95% confidence interval [CI], 1.71-4.68; p<0.001) and the presence of ischemic or organic heart diseases (HR=2.6; 95% CI, 1.21-5.43; p=0.014) were the strongest predictors of death, together with increasing age (HR=1.0; 95% CI, 1.0-1.06; p=0.033). Respiratory diseases and arrhythmias without organic heart diseases were negative predictors of full recovery of consciousness (odds ratio [OR]=0.3; 95% CI, 0.12-0.7; p=0.006; OR=0.2; 95% CI, 0.07-0.43; p<0.001) and functional improvement (OR=0.4; 95% CI, 0.15-0.85, p=0.020; OR=0.2; 95% CI, 0.08-0.45; p<0.001). Our data show that comorbidities are common in these patients and some of them influence recovery of consciousness and outcomes.

Bilateral remote cerebellar haemorrhage after spinal surgery: a case study and review of the literature.

BACKGROUND: Remote cerebellar haemorrhage is a rare and unpredictable complication after intracranial and spinal surgery, although less frequently found in the latter. The physiopathology of this phenomenon has not been definitely explained. OBJECTIVES: To describe and discuss the potential implications and pathomechanism of a bilateral remote cerebellar haemorrhage case after spinal surgery and review the literature related to this rare phenomenon. CASE REPORT: A 75 year-old man developed bilateral remote cerebellar haemorrhage after a lumbar laminectomy. Brain CT and MRI examinations showed chronic bilateral remote cerebellar haemorrhage, right haemoventricle and bilateral supratentorial subarachnoid haemorrhage. Subsequently, the patient underwent rehabilitation therapy with improvement of symptoms. CONCLUSION: When large cerebrospinal fluid loss is observed during spinal surgery, brain imaging study should be carried out. The pathogenetic hypothesis of microcirculation vessels tearing, the role of previous spinal surgery and of cerebellar atrophy should be considered and validated with further investigation.

Pharmacological modulation of the state of awareness in patients with disorders of consciousness: an overview.

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.

Mechanisms of cortical neural synchronization related to healthy and impaired consciousness: evidence by quantitative electroencephalographic studies.

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.

Silencing the brain may be better than stimulating it. The GABA effect.

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 perception of pain and its management in disorders of consciousness.

One of the most controversial issues in the management of patients in a vegetative state or a minimally conscious state concerns their hypothetical capacity to continue to experience pain despite an apparent absence of self- and environmental awareness. Recent functional neuroimaging studies have shown a greater perception of pain in patients in minimally conscious state compared with patients in vegetative state, suggesting the possible involvement of preserved cognitive mechanisms in the process of pain modulation in the former. In addition, a subgroup of patients might continue to experience some elementary emotional and affective feelings, as suggested by the reported activation of specific cerebral areas in response to situations, which commonly generate empathy. However, the available evidence is not sufficient to draw conclusions about the presence or absence of pain experience in patients with disorders of consciousness. Future studies should contribute to a better understanding of which central neural pathways are involved in the perception and modulation of pain in healthy subjects and in patients with severe brain injuries. Such studies should thus also improve our know-how about pain management in this particularly challenging group of patients.

Explicit recognition of emotional facial expressions is shaped by expertise: evidence from professional actors.

Can reading others' emotional states be shaped by expertise? We assessed processing of emotional facial expressions in professional actors trained either to voluntary activate mimicry to reproduce character's emotions (as foreseen by the "Mimic Method"), or to infer others' inner states from reading the emotional context (as foreseen by "Stanislavski Method"). In explicit recognition of facial expressions (Experiment 1), the two experimental groups differed from each other and from a control group with no acting experience: the Mimic group was more accurate, whereas the Stanislavski group was slower. Neither acting experience, instead, influenced implicit processing of emotional faces (Experiment 2). We argue that expertise can selectively influence explicit recognition of others' facial expressions, depending on the kind of "emotional expertise".