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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.

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 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; p0.001) 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; p0.001) and functional improvement (OR=0.4; 95% CI, 0.15-0.85, p=0.020; OR=0.2; 95% CI, 0.08-0.45; p0.001). Our data show that comorbidities are common in these patients and some of them influence recovery of consciousness and outcomes.

Progress in medical science and technology drastically improved physicians’ ability to interact with patient’s physical body. Nevertheless, medicine still addresses the human body from a Hippocratic point of view, considering the organism and its processes just as a matter of mechanics and fluids. However, the interaction between the cognitive neuroscience of bodily self-consciousness (BSC), fundamentally rooted in the integration of multisensory bodily inputs, with virtual reality (VR), haptic technologies and robotics is giving a new meaning to the classic Juvenal’s latin dictum “Mens sana in corpore sano” (a healthy mind in a healthy body). This vision provides the basis for a new research field, “Embodied Medicine”: the use of advanced technologies for altering the experience of being in a body with the goal of improving health and well-being. Up to now, most of the research efforts in the field have been focused upon how external bodily information is processed and integrated. Despite the important results, we believe that existing bodily illusions still need to be improved to enhance their capability to effectively correct pathological dysfunctions. First, they do not follow the suggestions provided by the free-energy and predictive coding approaches. More, they lacked to consider a peculiar feature of the human body, the multisensory integration of internal inputs (interoceptive, proprioceptive and vestibular) that constitute our inner body dimension. So, a future challenge is the integration of simulation/stimulation technologies also able to measure and modulate this internal/inner experience of the body. Finally, we also proposed the concept of “Sonoception” as an extension of this approach. The core idea is to exploit recent technological advances in the acoustic field to use sound and vibrations to modify the internal/inner body experience.

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.

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.

Chronic smoking is associated with functional and structural vascular changes underlying inflammatory processes responsible for plaque formation and rupture. Cyclooxygenase (COX) is the key enzyme linking smoking action to inflammatory damages: it is responsible for the conversion of arachidonic acid to prostanoids, and lipid mediators involved in most of pathological processes. Two COX isoenzymes have been characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, and preferential coupling to upstream and downstream enzymes. The aim of this review is to highlight the pathogenetic role of chronic smoking in vasomotor dysfunction, inflammation, and modification of lipids underlying the initiation and the progression of atherosclerosis and to remark the hypothesis that plaque composition rather than plaque size is the real determinant of the plaque evolution toward rupture and the major responsible for acute ischemic syndromes. The concomitantly higher expression of EP4, COX-2, mPGES-1, MMP-2 and MMP-9 in unstable plaques is focused and the role of PGE(2) as pathophysiological link between smoking, COX-2 and MMP activity is stressed. Indeed, the intracellular pathways regulating COX-2 and the mechanisms suggested to clarify the role of COX-2 and downstream synthases in atherothrombosis are summarized.

The amyloid cascade hypothesis sustains that beta-amyloid (Aβ) is the main pathogenetic factor of Alzheimers Disease (AD). Although the direct and indirect neurotoxic role of Aβ are unchallenged, recent findings suggest that the peptide may have so far unforeseen physiological roles. In this regard, the observations showing the ability of Aβ to exert synaptic activities in absence of neurotoxicity are very intriguing. In particular, the peptide is able to affect synaptic transmission of different neurotransmitter systems in key brain areas that regulate executive and cognitive functions, an observation that points Aβ as a new neuromodulator. However, in a pathological context, Aβ may drive functional alterations of several neurotransmitter systems in the early phases of the disease, in turn producing subtle cognitive and behavioural disturbances in addition and before the well known neurodegenerative events. On the other hand, advancing age is the most significant risk factor for the development of AD. In fact, during aging increased Aβ levels have been reported. Moreover, several neurotransmitter systems undergo age-related changes in parallel to a decline of cognitive functions. However, the putative neuromodulatory role of Aβ in the context of aging is nowadays unknown. For these reasons, future studies about the spectrum of action of Aβ (brain areas and neurotransmitter systems affected) are particularly interesting since may suggest new therapeutic targets in order to sustain those functions which may be altered during aging.

In the present study, we demonstrated that observation of hand rotation had specific facilitation effects on a classical motor imagery task, the hand-laterality judgement. In Experiment 1, we found that action observation improved subjects' performance on the hand laterality but not on the letter rotation task (stimulus specificity). In Experiment 2, we demonstrated that this facilitation was not due to mere observation of a moving hand, because it was triggered by observation of manual rotation but not of manual prehension movements (motion specificity). In Experiment 3, this stimulus- and motion-specific effect was found to be right hand-specific, compatible with left-hemispheric specialization in motor imagery but not in action observation. These data provided direct support to the idea that different simulation states, such as action observation and motor imagery, share some common mechanisms but also show specific functional differences.

Sara M, Pistoia F, Mura E, Onorati P, Govoni S. Intrathecal baclofen in patients with persistent vegetative state: 2 hypotheses. Arch Phys Med Rehabil 2009;90:1245-9. Sporadic cases of recovery from persistent vegetative state (PVS) after administration of intrathecal baclofen (ITB) have been reported without giving any possible explanation for its paradoxical effect. We summarize our recent findings on 5 patients with PVS treated with ITB and make some specula- tions on the mechanisms responsible for the observed clinical improvement. The patients developed spasticity and were judged eligible for ITB therapy. Two weeks after pump im- plantation, patients began to show a clinical improvement that, at the end of the 6 months' follow-up, was stable in all but 1 patient, ranging from a mere increased alertness to a full recovery of consciousness, as revealed by changes of the Coma Recovery Scale-Revised (CRS-R) score. Our findings suggest that ITB might favor a variable degree of clinical improvement. A proposal for a pharmacodynamic explanation of this effect has not been formally put forward. We hypothesize 2 possible mechanisms: first, a modulation confined to spinal cord seg- mental activities and to neuronal centripetal outputs reaching the cortex; and second, a modulation of sleep-wake cycles that, although present, may be dysregulated and interfere with alert- ness and awareness. Although our research is confined to a few subjects, it provides follow-up information by means of the CRS-R that is a validated standardized neurobehavioral instru- ment expressly designed for use in patients with PVS. Our observations indicate that further systematic investigation of the mechanisms and the putative clinical applications of ITB should be undertaken.

Recent studies indicate that motor imagery is subserved by activation of motor information. However, at present it is not clear whether the sparing of motor efferent pathways is necessary to perform a motor imagery task. To clarify this issue, we required patients with a selective, severe de-efferentation (locked-in syndrome, LIS) to mentally manipulate hands and three-dimensional objects. Compared with normal controls, LIS patients showed a profound impairment on a modified version of the hand-laterality task and a normal performance on mental rotation of abstract items. Moreover, LIS patients did not present visuomotor compatibility effects between anatomical side of hands and spatial location of stimuli on the computer screen. Such findings confirmed that the motor system is involved in mental simulation of action but not in mental manipulation of visual images. To explain LIS patients' inability in manipulating hand representations, we suggested that the pontine lesion, both determined a complete de-efferentation, and affected a component of the motor system, which is crucial for mental representation of body parts, probably the neural connections between parietal lobes and cerebellum.

Electroencephalography (EEG) and somatosensory potentials (SEP) are regarded as useful tools for exploring residual brain activity and providing information for recovery in patients with anoxic encephalopaty. However, the diagnoses of vegetative and minimally conscious states can only be made by means of repeated specific neurological examinations. In this respect, this study describes the case of a patient with mismatch of neurophysiological findings despite partial recovery to a minimally conscious state.A 52-year-old man was admitted to the Post-Coma Intensive and Rehabilitation Care Unit with a diagnosis of anoxic encephalopathy. EEG, according to Hockaday, was severely abnormal (Grade IVa). SEP showed bilateral loss of all cortical components. Four weeks after admission the Coma Recovery Scale Revised (CRS-R) score moved from 7/23 to 13/23.This patient persistently showed a mismatch of neurophysiological findings which did not anticipate the slight but discriminating improvement ascertained through the neurological examination. This observation confirms that electrophysiological evaluations can only be regarded as ancillary tools since level of consciousness may be reliably evaluated only by means of repeated specific neurological assessments. As this case-report suggests, neurophysiological findings may turn out to be inconclusive and misleading in relation to the assessment of consciousness and may lead to an underestimate of minimal signs of recovery across the grey-zone from the vegetative to the minimally conscious state.

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.

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.

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.

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.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.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.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.

Primary objective: To challenge the Multi-Society Task Force's ruling that a persistent vegetative state (PVS) can be judged to be permanent for non traumatic brain injury after three months.Method: We report the case of a 44-year-old man who had recovery of consciousness with persistent severe disability 19 months after a non-traumatic brain injury at least in part triggered and maintained by intrathecal baclofen administration.Result: This unexpected and late recovery of consciousness raises an interesting hypothesis of possible effects of partially regained spinal cord outputs on reactivation of cognition.Conclusion: Considering that several ethical, legal, and socio-economic issues have been raised about the opportunity of withdrawing treatment and life support in patients with PVS the report of this case might add further documentation to the ongoing debate.

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.

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”. These results demonstrate that not only simulative processes involved in action recognition but also those related to more complex aspects of social cognition (such as emotion recognition) can be affected by expertise.

Objective To investigate whether corticomotor facilitation induced by transcranial magnetic stimulation (TMS-CF) could evoke a simple purposeful motor behavior in patients with a diagnosis of vegetative state. Design Cross-sectional survey. Setting Post-coma and rehabilitation care unit. Participants Patients (N=6) with a diagnosis of vegetative state. Interventions A cascade of consecutive motor-evoked potentials (MEPs) was elicited under 3 different conditions: in the first condition, patients were at rest (Rest); in the second, they were asked to open and close the right hand (Execution); in the third, the examiner modeled a movement of abduction of the thumb in front of the patient who was encouraged in advance to imitate the action (Observation to Imitate). Main Outcome Measures Changes in MEP values from the abductor pollicis brevis muscle and improvement in scores on the Coma Recovery Scale-Revised. Results TMS-CF alone or combined with verbal instructions did not yield any change; only the combination with imitation caused changes in MEPs (shorter latency and increased amplitude) associated with behavioral improvement in 4 patients. Conclusions Encouraging observation to imitate may favor the transformation of some perceived actions into motor images and performances, probably depending on the activation of mirror motor neurons. In our opinion, combining visual input with TMS-CF might have reinforced the coupling between movement planning and execution, promoting the recovery of elementary motor activities in some patients. The proposed protocol may contribute to unmasking signs of preserved consciousness in patients with latent capacities for recovery.

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.

Patients with locked-in syndrome, although fully conscious, have quadriplegia, mutism, and lower cranial nerve paralysis. The preservation of vertical gaze and upper eyelid movements usually enables them to interact with the environment through an eye-coded communication. However, locked-in syndrome may be complicated by the development of an opsoclonus-myoclonus syndrome that may represent an additional impediment to communication. We evaluated whether off-label treatment with gabapentin could help patients with locked-in syndrome and opsoclonus-myoclonus symptoms regain voluntary control of full eye movements. A mechanism responsible for gabapentin-induced improvement has been also hypothesized. In this study, 4 patients presenting with locked-in syndrome complicated by opsoclonus-myoclonus syndrome were continuously treated with gabapentin up to 1200 mg/d. The treatment resulted in a rapid and long-lasting resolution of opsoclonus-myoclonus symptoms without adverse effects. After 2 weeks, patients showed voluntary attempts to communicate through eye blinking and thereafter regained voluntary control of full eye movements. This event enabled them to regain a communication channel with relatives and physicians and to start using eye-controlled brain-computer interfaces. Because of its effectiveness in restoring eye movement control, gabapentin opened a communicative porthole in the patients' lives. Since opsoclonus may be related to disorders of the inhibitory control of saccadic burst neurons by pontine pause cells, we hypothesize that gabapentin acts as a regulator of saccadic circuits.

Several lines of evidence demonstrate that the motor system is involved in motor simulation of actions, but some uncertainty exists about the consequences of lesions of descending motor pathways on mental imagery tasks. Moreover, recent findings suggest that the motor system could also have a role in recognition of body parts. To address these issues in the present study we assessed patients with a complete damage of descending motor pathways (locked-in syndrome, LIS) on the hand laterality task, requiring subjects to decide whether a hand stimulus in a given spatial orientation represents a left or a right hand. LIS patients were less accurate than healthy controls in judging hand laterality; more importantly, LIS patients' performance was modulated by spatial orientation of hand stimuli whereas it was not affected by biomechanical constraints. These findings demonstrate a dissociation between spared hand recognition and impaired access to action simulation processes in LIS patients.

Disorders of consciousness (DOC) include coma, vegetative state (VS) and minimally conscious state (MCS). Coma is a condition of unarousability with a complete absence of wakefulness and awareness, whereas VS is characterized by a lack of awareness despite a preserved wakefulness. Patients in coma are unconscious because they lack both wakefulness and awareness. Patients in a VS are unconscious because, although they are wakeful, they lack awareness. Patients in a MCS show minimal but definite behavioural evidence of self and environmental awareness. Coma results from diffuse bilateral hemispheric lesions or selective damage to the ascending reticular system (which is functionally connected to the cerebral cortex by intralaminar thalamic nuclei). VS is a syndrome that is considered to be the result of a disconnection of different cortical networks rather than a dysfunction of a single area or a global reduction in cortical metabolism. As revealed by functional imaging studies, clinical recovery is often associated with a functional restoration of cortico-thalamo-cortical connections. Depending on the amount of network restored, patients may regain full consciousness or remain in a MCS. Molecular and neural mediators may indirectly contribute to the above restoration processes owing to their role in the phenomenon of neural synaptic plasticity. Therefore, there is growing interest in the possible effects of drugs that act at the level of the CNS in promoting emergence from DOC. Sporadic cases of dramatic recovery from DOC after the administration of various pharmacological agents, such as baclofen, zolpidem and amantadine, have been recently supported by intriguing scientific observations. Analysis of the reported cases of recovery, with particular attention paid to the condition of the patients and to the association of their improvement with the start of drug administration, suggests that these treatments might have promoted the clinical improvement of some patients. These drugs are from various and diverging classes, but can be grouped into two main categories, CNS stimulants and CNS depressants. Some of these treatments seem to directly encourage a consciousness restoration, while others play a more determinant role in improving cognitive domains, especially in patients with residual cognitive impairment, than in the field of consciousness. Given the great interest recently generated in the scientific community by the increasing number of papers addressing this issue, further investigation of the above treatments, with particular attention paid to their mechanisms of action, the neurotransmitters involved and their effects on cortico-thalamo-cortical circuitry, is needed.

Objective: Previous studies have been inconclusive whether dominant resting state alpha rhythms are greater or lower in amplitude in subjects with Down syndrome (DS) when compared to control subjects, ample resting alpha rhythms being considered as a reflection of good mechanisms of cortical neural synchronization. Here we tested the hypothesis that when the effects of head volume conduction are taken into account by the normalization of the cortical sources of resting alpha rhythms, these sources are lower in amplitude in DS subjects than in controls in line with typical findings in Alzheimer’s disease patients. Methods: Eyes-closed resting electroencephalographic (EEG) data were recorded in 45 DS subjects (25 males; mean age of 22.8 years ± 0.7 standard error of mean (SEM)) and in 45 age-matched cognitively normal subjects (25 males; mean age of 22.4 years ± 0.5 SEM). EEG rhythms of interest were delta (2– 4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), beta 2 (20–30 Hz), and gamma (30–40 Hz). Cortical EEG sources were estimated by low resolution electromagnetic tomography (LORETA) and normalized across all voxels and frequencies. Results: Central, parietal, occipital, and temporal cortical sources of resting alpha and beta rhythms were lower in amplitude in the DS than control subjects, whereas the opposite was true for occipital delta cortical sources. A control analysis on absolute source values showed that they were globally larger in amplitude across several frequency bands in DS than control subjects. Conclusions: These results suggest that normalized cortical sources of alpha rhythms are lower in amplitude in DS than control subjects, as it is typically found in Alzheimer’s disease. Significance: DS is accompanied by a functional impairment of cortical neuronal synchronization mechanisms in the resting state condition.

Objective Locked-in syndrome (LIS) is a state of complete paralysis, except for ocular movements, which results from ventral brainstem lesions. Patients typically are fully conscious. Here we tested the hypothesis that electroencephalographic (EEG) rhythms are abnormal in LIS patients, possibly due to an impaired neural synchronization between brainstem and cerebral cortex. Methods Resting state eyes-closed EEG data were recorded in 13 LIS subjects and 15 cognitively normal control subjects. With reference to the individual alpha frequency (IAF), the bands of interest were delta (IAF-8 to IAF-6 Hz), theta (IAF-6 to IAF-4 Hz), alpha 1 (IAF-4 to IAF-2 Hz), alpha 2 (IAF-2 to IAF Hz), and alpha 3 (IAF to IAF + 2 Hz). Furthermore, beta 1 (13–20 Hz) and beta 2 (20–30 Hz) bands were also considered. Cortical EEG sources were estimated by low-resolution electromagnetic tomography (LORETA). Results The power of alpha 2 and alpha 3 sources in all regions was lower in patients with LIS compared to controls. The power of delta sources in central, parietal, occipital and temporal regions was higher in patients with LIS compared to controls. Conclusions These results suggest that cortical sources of resting state eyes-closed alpha and delta rhythms are abnormal in LIS patients. Significance LIS is accompanied by a functional impairment of cortical neuronal synchronization mechanisms in the resting state condition.

The involvement of facial mimicry in different aspects of human emotional processing is widely debated. However, little is known about\ud relationships between voluntary activation of facial musculature and conscious recognition of facial expressions. To address this issue,\ud we assessed severely motor-disabled patients with complete paralysis of voluntary facial movements due to lesions of the ventral pons\ud [locked-in syndrome (LIS)]. Patients were required to recognize others’ facial expressions and to rate their own emotional responses to\ud presentation of affective scenes.LISpatientswere selectivelyimpairedin recognition of negativefacial expressions,thusdemonstratingthatthe\ud voluntary activation of mimicry represents a high-level simulation mechanism crucially involved in explicit attribution of emotions.

Recurrent bleedings of cavernous malformations are quite frequent and frightful: survival is especially at risk in patients with brainstem cavernous malformations who cannot benefit from neurosurgical treatments. Nevertheless, pragmatic recommendations to prevent recurrent bleedings are still lacking, raising some questions on the daily clinical management of the above patients.This study reports the case of a 59 year-old woman presenting with past recurrent bleedings from a brainstem cavernous malformation and with indication to start an anti-thrombotic treatment as a consequence of a developing coronary heart disease. Surprisingly, any suggestion about the usage of otherwise indicated anti-platelet treatment and anti-coagulation in patients with cavernous malformations was found in the literature.The authors faced a therapeutical dilemma with this patient, whose survival would be really at risk because of a 'time bomb in her brainstem'.This experience confirms the lack of clear pragmatic recommendations in the clinical management of these patients, whose treatment still represents a medical challenge.

Consciousness has not yet been satisfactorily defined because of its puzzling nature which involve the perception of the environment (perceptual awareness) and of the self (self-awareness). Current available methods fail in establishing prognosis in patients with vegetative state (VS): to our mind, this failure stems from the heterogeneous localization of brain damages causing VS and from available approaches tending to investigate self-awareness separately from perceptual awareness, whereas consciousness should be explored as a single and indivisible whole. Moving from the assumption that consciousness depends on the normal activity of wide neural networks, that may be regarded as complex systems whose outputs show a nonlinear behaviour, we propose a nonlinear approach applied to electroencephalographic (EEG) signal, aimed at exploring residual neural networks complexity in patients with VS. For this objective the EEG recording of 10 patients previously admitted to our department were retrospectively analyzed and compared with those of ten matched healthy control subjects. Approximate Entropy (ApEn) was calculated from the average values of time series with fixed input variables. Mean ApEn values were lower in patients than in controls (t18 18 = 12.3, p0.001). ApEn is able to discriminate patients from controls thus supporting the hypothesis about a decreased neural networks complexity in VS.

The experience with a patient with locked-in syndrome suffering from opsoclonus—myoclonus symptoms is described: gabapentin successfully reversed the symptoms, just favoring the regaining of eye-dependent communication strategies.

Objective High power of pre-stimulus cortical alpha rhythms (about 8–12 Hz) underlies conscious perception in normal subjects. Here we tested the hypothesis that these rhythms are abnormal in persistent vegetative state (PVS) patients, who are awake but not aware of self and environment. Methods Clinical and resting-state, eyes-closed electroencephalographic (EEG) data were taken from a clinical archive. These data were recorded in 50 PVS subjects (level of cognitive functioning – LCF score: I–II) and in 30 cognitively normal subjects. Rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). Cortical sources were estimated by low-resolution electromagnetic tomography (LORETA). Based on LCF score at 3-months follow-up, PVS patients were retrospectively divided into three groups: 30 subjects who did not recover (NON-REC patients; follow-up LCF: I–II), 8 subjects classified as minimally conscious state patients (MCS patients; follow-up LCF: III–IV), and 12 subjects who recovered (REC patients; follow-up LCF: V–VIII). Results Occipital source power of alpha 1 and alpha 2 was high in normal subjects, low in REC patients, and practically null in NON-REC patients. A Cox regression analysis showed that the power of alpha source predicted the rate of the follow up recovery, namely the higher its power, the higher the chance to recover consciousness. Furthermore, the MCS patients showed intermediate values of occipital alpha source power between REC and NON-REC patients. Conclusions These results suggest that cortical sources of alpha rhythms are related to the chance of recovery at a 3-months follow-up in patients in persistent vegetative state. Significance Cortical sources of resting alpha rhythms might predict recovery in PVS patients.