Long-term clinical evolution of patients with prolonged disorders of consciousness due to severe anoxic brain injury: A meta-analytic study.

BACKGROUND AND PURPOSE: The prognosis of prolonged (28 days to 3 months post-onset) disorders of consciousness (pDoC) due to anoxic brain injury is uncertain. The present study aimed to evaluate the long-term outcome of post-anoxic pDoC and identify the possible predictive value of demographic and clinical information. METHOD: This is a systematic review and meta-analysis. The rates of mortality, any improvement in clinical diagnosis, and recovery of full consciousness at least 6 months after severe anoxic brain injury were evaluated. A cross-sectional approach searched for differences in baseline demographic and clinical characteristics between survivors and non-survivors, patients improved versus not improved, and patients who recovered full consciousness versus not recovered. RESULTS: Twenty-seven studies were identified. The pooled rates of mortality, any clinical improvement and recovery of full consciousness were 26%, 26% and 17%, respectively. Younger age, baseline diagnosis of minimally conscious state versus vegetative state/unresponsive wakefulness syndrome, higher Coma Recovery Scale Revised total score, and earlier admission to intensive rehabilitation units were associated with a significantly higher likelihood of survival and clinical improvement. These same variables, except time of admission to rehabilitation, were also associated with recovery of full consciousness. CONCLUSIONS: Patients with anoxic pDoC might improve over time up to full recovery of consciousness and some clinical characteristics can help predict clinical improvement. These new insights could support clinicians and caregivers in the decision-making on patient management.

The Consciousness Domain Index: External Validation and Prognostic Relevance of a Data-Driven Assessment.

The prognosis of neurological outcomes in patients with prolonged Disorders of Consciousness (pDoC) has improved in the last decades. Currently, the level of consciousness at admission to post-acute rehabilitation is diagnosed by the Coma Recovery Scale-Revised (CRS-R) and this assessment is also part of the used prognostic markers. The consciousness disorder diagnosis is based on scores of single CRS-R sub-scales, each of which can independently assign or not a specific level of consciousness to a patient in a univariate fashion. In this work, a multidomain indicator of consciousness based on CRS-R sub-scales, the Consciousness-Domain-Index (CDI), was derived by unsupervised learning techniques. The CDI was computed and internally validated on one dataset (N=190) and then externally validated on another dataset (N=86). Then, the CDI effectiveness as a short-term prognostic marker was assessed by supervised Elastic-Net logistic regression. The prediction accuracy of the neurological prognosis was compared with models trained on the level of consciousness at admission based on clinical state assessments. CDI-based prediction of emergence from a pDoC improved the clinical assessment-based one by 5.3% and 3.7%, respectively for the two datasets. This result confirms that the data-driven assessment of consciousness levels based on multidimensional scoring of the CRS-R sub-scales improve short-term neurological prognosis with respect to the classical univariately-derived level of consciousness at admission.

Consciousness-Domain Index: a data-driven clustering-based consciousness labeling.

Assessing consciousness results in one of the most complex neurological diagnosis. Even more complex and uncertain is prognosticating on consciousness recovery. Currently, consciousness is assessed by using a six-items scale, the Coma Recovery Scale-Revised. Namely, scores on the sub-items can individually assign or not a specific level of consciousness to a patient. In our work, by using solely the six sub-items of the CRS-R, we implemented a clustering algorithm labeling patients with the Consciousness-Domains Index (CDI) starting from a dataset of 190 patients with a Disorder of Consciousness (DoC). Then, the CDI is compared with the clinical state at admission and at six months via univariate analysis. The number of clusters best dividing the groups resulted equal to two and the most influencing sub-items resulted the visual and motor one. The CDI closely resembles the clinical state at admission (CSA) (Cohen's k=0.85). On the other hand, when comparing CDI and CSA, a net improvement was found in the prognostic power of the neurological outcome at six months, targeted as presence/absence of a DoC ( ). Data-driven techniques pave the way for automated and model-based search of prognostic factors, together with the use of such prognostic factors in multivariate prognostic models. Future works will address the external validation of the CDI, together with the inclusion of the CDI in a multivariate supervised model, in order to assess the true potential of such novel index. Clinical Relevance- A completely data-driven index was derived from a clustering of CRS-R sub-items. It correlates with the neurological outcome at six months better than the state of consciousness at admission.

What names for covert awareness? A systematic review.

Background: With the emergence of Brain Computer Interfaces (BCI), clinicians have been facing a new group of patients with severe acquired brain injury who are unable to show any behavioral sign of consciousness but respond to active neuroimaging or electrophysiological paradigms. However, even though well documented, there is still no consensus regarding the nomenclature for this clinical entity. Objectives: This systematic review aims to 1) identify the terms used to indicate the presence of this entity through the years, and 2) promote an informed discussion regarding the rationale for these names and the best candidates to name this fascinating disorder. Methods: The Disorders of Consciousness Special Interest Group (DoC SIG) of the International Brain Injury Association (IBIA) launched a search on Pubmed and Google scholar following PRISMA guidelines to collect peer-reviewed articles and reviews on human adults (>18 years) published in English between 2006 and 2021. Results: The search launched in January 2021 identified 4,089 potentially relevant titles. After screening, 1,126 abstracts were found relevant. Finally, 161 manuscripts were included in our analyses. Only 58% of the manuscripts used a specific name to discuss this clinical entity, among which 32% used several names interchangeably throughout the text. We found 25 different names given to this entity. The five following names were the ones the most frequently used: covert awareness, cognitive motor dissociation, functional locked-in, non-behavioral MCS (MCS*) and higher-order cortex motor dissociation. Conclusion: Since 2006, there has been no agreement regarding the taxonomy to use for unresponsive patients who are able to respond to active neuroimaging or electrophysiological paradigms. Developing a standard taxonomy is an important goal for future research studies and clinical translation. We recommend a Delphi study in order to build such a consensus.

Predicting outcome of patients with prolonged disorders of consciousness using machine learning models based on medical complexity.

Patients with severe acquired brain injury and prolonged disorders of consciousness (pDoC) are characterized by high clinical complexity and high risk to develop medical complications. The present multi-center longitudinal study aimed at investigating the impact of medical complications on the prediction of clinical outcome by means of machine learning models. Patients with pDoC were consecutively enrolled at admission in 23 intensive neurorehabilitation units (IRU) and followed-up at 6 months from onset via the Glasgow Outcome Scale-Extended (GOSE). Demographic and clinical data at study entry and medical complications developed within 3 months from admission were collected. Machine learning models were developed, targeting neurological outcomes at 6 months from brain injury using data collected at admission. Then, after concatenating predictions of such models to the medical complications collected within 3 months, a cascade model was developed. One hundred seventy six patients with pDoC (M: 123, median age 60.2 years) were included in the analysis. At admission, the best performing solution (k-Nearest Neighbors regression, KNN) resulted in a median validation error of 0.59 points [IQR 0.14] and a classification accuracy of dichotomized GOS-E of 88.6%. Coherently, at 3 months, the best model resulted in a median validation error of 0.49 points [IQR 0.11] and a classification accuracy of 92.6%. Interpreting the admission KNN showed how the negative effect of older age is strengthened when patients' communication levels are high and ameliorated when no communication is present. The model trained at 3 months showed appropriate adaptation of the admission prediction according to the severity of the developed medical complexity in the first 3 months. In this work, we developed and cross-validated an interpretable decision support tool capable of distinguishing patients which will reach sufficient independence levels at 6 months (GOS-E > 4). Furthermore, we provide an updated prediction at 3 months, keeping in consideration the rehabilitative path and the risen medical complexity.

Development of an Italian version of the functional communication measures and preliminary observations in patients with severe acquired brain injury and emerging from a prolonged disorder of consciousness.

A proper assessment tool targeting communicative abilities in patients with severe acquired brain injury (sABI), and particularly for patients recovering from prolonged disorders of consciousness (pDoC), is lacking. The Functional Communication Measures (FCM) consists of a series of rating scales, ranging from 1 (least functional) to 7 (most functional), assessing cognitive requirements for communication and communicative abilities in patients with brain injury. Here we presented exploratory data concerning an Italian adaptation of FCM administered to patients with sABI. After the translation into Italian language, the FCM was blindly administered by 2 independent speech therapists to 19 patients (10 males; median age = 58; IQR = 25) admitted to neurorehabilitation unit after sABI with a level of cognitive functioning between 4 and 8. Two further patients who presented a pDoC after sABI and emerged from the minimally conscious state (a 64-year-old female and a 74-year-old female) were also evaluated by means of the FCM, the Coma Recovery Scale-Revised, and the Disability Rating Scale. Inter-rater agreement was almost perfect for attention, memory, and swallowing items, and substantial for communicative-augmentative communication, motor speech, spoken language expression, and spoken language comprehension. Importantly, in the two pDoC patients, the FCM identified two different functioning profiles in the attention, swallowing, motor speech, and spoken language expression scales, notwithstanding the two patients achieved the same scores on scales for functional disability and consciousness level. The FCM might be a promising and easy-to-administer tool to assess communicative functions in patients with sABI, independently from evaluation of functional disability.

Clinical, Neurophysiological, and Genetic Predictors of Recovery in Patients With Severe Acquired Brain Injuries (PRABI): A Study Protocol for a Longitudinal Observational Study.

Background: Due to continuous advances in intensive care technology and neurosurgical procedures, the number of survivors from severe acquired brain injuries (sABIs) has increased considerably, raising several delicate ethical issues. The heterogeneity and complex nature of the neurological damage of sABIs make the detection of predictive factors of a better outcome very challenging. Identifying the profile of those patients with better prospects of recovery will facilitate clinical and family choices and allow to personalize rehabilitation. This paper describes a multicenter prospective study protocol, to investigate outcomes and baseline predictors or biomarkers of functional recovery, on a large Italian cohort of sABI survivors undergoing postacute rehabilitation. Methods: All patients with a diagnosis of sABI admitted to four intensive rehabilitation units (IRUs) within 4 months from the acute event, aged above 18, and providing informed consent, will be enrolled. No additional exclusion criteria will be considered. Measures will be taken at admission (T0), at three (T1) and 6 months (T2) from T0, and follow-up at 12 and 24 months from onset, including clinical and functional data, neurophysiological results, and analysis of neurogenetic biomarkers. Statistics: Advanced machine learning algorithms will be cross validated to achieve data-driven prediction models. To assess the clinical applicability of the solutions obtained, the prediction of recovery milestones will be compared to the evaluation of a multiprofessional, interdisciplinary rehabilitation team, performed within 2 weeks from admission. Discussion: Identifying the profiles of patients with a favorable prognosis would allow customization of rehabilitation strategies, to provide accurate information to the caregivers and, possibly, to optimize rehabilitation outcomes. Conclusions: The application and validation of machine learning algorithms on a comprehensive pool of clinical, genetic, and neurophysiological data can pave the way toward the implementation of tools in support of the clinical prognosis for the rehabilitation pathways of patients after sABI.

Implicit Motor Imagery and the Lateral Occipitotemporal Cortex: Hints for Tailoring Non-Invasive Brain Stimulation.

BACKGROUND: Recent evidence has converged in showing that the lateral occipitotemporal cortex is over-recruited during implicit motor imagery in elderly and in patients with neurodegenerative disorders, such as Parkinson's disease. These data suggest that when automatically imaging movements, individuals exploit neural resources in the visual areas to compensate for the decline in activating motor representations. Thus, the occipitotemporal cortex could represent a cortical target of non-invasive brain stimulation combined with cognitive training to enhance motor imagery performance. Here, we aimed at shedding light on the role of the left and right lateral occipitotemporal cortex in implicit motor imagery. METHODS: We applied online, high-frequency, repetitive transcranial magnetic stimulation (rTMS) over the left and right lateral occipitotemporal cortex while healthy right-handers judged the laterality of hand images. RESULTS: With respect to the sham condition, left hemisphere stimulation specifically reduced accuracy in judging the laterality of right-hand images. Instead, the hallmark of motor simulation, i.e., the biomechanical effect, was never influenced by rTMS. CONCLUSIONS: The lateral occipitotemporal cortex seems to be involved in mental representation of the dominant hand, at least in right-handers, but not in reactivating sensorimotor information during simulation. These findings provide useful hints for developing combined brain stimulation and behavioural trainings to improve motor imagery.

Sex differences in implicit motor imagery: Evidence from the hand laterality task.

Behavioural evidence suggest that males outperform females in mentally transforming objects, whereas whether sex differences exist in mentally transforming body part images (implicit motor imagery) is an open issue. The aim of the present study was to fill this gap testing performance of 360 healthy participants on a classical behavioural measure of implicit motor imagery: the hand laterality task. Participants had to judge handedness of hand images portrayed from back and palm and presented in different spatial orientations. Two main findings emerged. First, males were significantly faster than females in judging hands portrayed from palm, in particular left palms at 0°, 90° and 180° orientation, whereas females were faster than males in judging backs, in particular left and right backs at 0° and the left back at 90°. Second, both males and females showed a significant biomechanical effect (faster responses for hands portrayed in medial vs. lateral positions) while judging palms, albeit the effect was stronger in males, whereas only females showed a significant biomechanical effect when judging backs. Thus, males and females seem to differently exploit motor simulation processes during mental transformation of hand images depending on a specific familiarity with body parts portrayed from different views. This result might be taken into account when tailoring motor imagery tasks in applied contexts, as motor rehabilitation.

Left inferior parietal and posterior temporal cortices mediate the effect of action observation on semantic processing of objects: evidence from rTMS.

Previous studies showed that motor information related to tool use (i.e., functional actions) could affect processing of objects semantic properties, whereas motor information related to grasping or moving tool (i.e., structural actions) cannot. However, little is known about the neural correlates mediating such interaction between motor and semantic information. Here, healthy participants performed a semantic judgment task requiring identification of semantic relations among objects, after observing a functional, a structural or a pointing action prime. In a within-subject design, during prime presentation the participants underwent repetitive transcranial magnetic stimulation (rTMS) over the left supramarginal gyrus (SMG), the left posterior middle temporal gyrus (pMTG) or received sham stimulation. Results showed that in the sham condition observing functional actions (vs. structural and pointing actions) favoured processing of semantic relations based on function similarity (i.e., taxonomic relations), but not of relations based on co-occurrence within an event schema (i.e., thematic relations). Moreover, stimulation of both left SMG and pMTG abolished the effect of functional action primes worsening subsequent judgment about taxonomic relations, and this effect was greater after pMTG stimulation. rTMS did not affect processing of thematic semantic relations. We suggest that action observation triggers activation of functional motor information within left inferior parietal cortex, and that integration between functional motor and conceptual information in left temporal cortex could impact high-level semantic processing of tools.

Can Salient Stimuli Enhance Responses in Disorders of Consciousness? A Systematic Review.

PURPOSE OF REVIEW: Diagnostic classification of patients with disorders of consciousness (DoC) is based on clinician's observation of volitional behaviours. However, patients' caregivers often report higher levels of responsiveness with respect to those observed during the clinical assessment. Thus, increasing efforts have been aimed at comprehending the effects of self-referential and emotional stimuli on patients' responsiveness. Here we systematically reviewed the original experimental studies that compared behavioural and electrophysiological responses with salient vs. neutral material in patients in vegetative state/unresponsive wakefulness syndrome or in minimally conscious state. RECENT FINDINGS: Most of the reviewed studies showed that salient stimuli (i.e. patient's own or familiar faces, patient's own name, and familiar voices) seem to elicit a higher amount of behavioural or electrophysiological responses with respect to neutral pictures or sounds. Importantly, a quite high percentage of patients seem to respond to salient stimuli only. The present review could foster use of personally salient stimuli in assessing DoC. However, the low overall quality of evidence and some limitations in the general reviewing process might induce caution in transferring these suggestions into clinical practice.

"Like the palm of my hands": Motor imagery enhances implicit and explicit visual recognition of one's own hands.

A key point in motor imagery literature is that judging hands in palm view recruits sensory-motor information to a higher extent than judging hands in back view, due to the greater biomechanical complexity implied in rotating hands depicted from palm than from back. We took advantage from this solid evidence to test the nature of a phenomenon known as self-advantage, i.e. the advantage in implicitly recognizing self vs. others' hand images. The self-advantage has been actually found when implicitly but not explicitly judging self-hands, likely due to dissociation between implicit and explicit body representations. However, such a finding might be related to the extent to which motor imagery is recruited during implicit and explicit processing of hand images. We tested this hypothesis in two behavioural experiments. In Experiment 1, right-handed participants judged laterality of either self or others' hands, whereas in Experiment 2, an explicit recognition of one's own hands was required. Crucially, in both experiments participants were randomly presented with hand images viewed from back or from palm. The main result of both experiments was the self-advantage when participants judged hands from palm view. This novel finding demonstrate that increasing the "motor imagery load" during processing of self vs. others' hands can elicit a self-advantage in explicit recognition tasks as well. Future studies testing the possible dissociation between implicit and explicit visual body representations should take into account the modulatory effect of motor imagery load on self-hand processing.

Whose hand is this? Differential responses of right and left extrastriate body areas to visual images of self and others' hands.

The extrastriate body area (EBA) is involved in perception of human bodies and nonfacial body parts, but its role in representing body identity is not clear. Here, we used on-line high-frequency repetitive transcranial magnetic stimulation (rTMS) to test the role of EBA in self-other distinction. In Experiments 1 and 2 we compared rTMS of right EBA with stimulation of left ventral premotor cortex (vPM), whereas in Experiment 3 we compared stimulation of right and left EBA. RTMS was applied during a hand laterality task in which self or others' hand images were presented in first- versus third-person view (Experiments 1 and 3), or while participants had to explicitly recognize their own hands (Experiment 2) presented in first- versus third-person view. Experiment 1 showed that right EBA stimulation selectively speeded judgments on others' hands, whereas no effect of left vPM stimulation was found. Experiment 2 did not reveal any effect of rTMS. Experiment 3 confirmed faster responses on others' hands while stimulating right EBA and also showed an advantage when judging self with respect to others' hands during stimulation of left EBA. These results would demonstrate that EBA responds to morphological features of human body contributing to identity processing.

The brain and the subjective experience of time. A voxel based symptom-lesion mapping study.

The aim of the study was to identify the anatomical bases involved in the subjective experience of time, by means of a voxel based symptom-lesion mapping (VLSM) study on patients with focal brain damage. Thirty-three patients (nineteen with right-hemisphere lesions -RBD, and fourteen with left lesion- LBD) and twenty-eight non-neurological controls (NNC) underwent the semi-structured QUEstionnaire for the Subjective experience of Time (QUEST) requiring retrospective and prospective judgements on self-relevant time intervals. All participants also completed tests to assess general cognitive functioning and two questionnaires to evaluate their emotional state. Both groups of brain-damaged patients achieved significantly different scores from NNC on the time performance, without differences between RBD and LBD. VLSM showed a cluster of voxels located in the right inferior parietal lobule significantly related to errors in the prospective items. The lesion subtraction analysis revealed two different patterns possibly associated with errors in the prospective items (the right inferior parietal cortex, rolandic operculum and posterior middle temporal gyrus) and in the retrospective items (superior middle temporal gyrus, white matter posterior to the insula).

Body Constraints on Motor Simulation in Autism Spectrum Disorders.

Developmental data suggested that mental simulation skills become progressively dissociated from overt motor activity across development. Thus, efficient simulation is rather independent from current sensorimotor information. Here, we tested the impact of bodily (sensorimotor) information on simulation skills of adolescents with Autism Spectrum Disorders (ASD). Typically-developing (TD) and ASD participants judged laterality of hand images while keeping one arm flexed on chest or while holding both arms extended. Both groups were able to mentally simulate actions, but this ability was constrained by body posture more in ASD than in TD adolescents. The strong impact of actual body information on motor simulation implies that simulative skills are not fully effective in ASD individuals.

Observing functional actions affects semantic processing of tools: evidence of a motor-to-semantic priming.

Recent evidence shows that activation of motor information can favor identification of related tools, thus suggesting a strict link between motor and conceptual knowledge in cognitive representation of tools. However, the involvement of motor information in further semantic processing has not been elucidated. In three experiments, we aimed to ascertain whether motor information provided by observation of actions could affect processing of conceptual knowledge about tools. In Experiment 1, healthy participants judged whether pairs of tools evoking different functional handgrips had the same function. In Experiment 2 participants judged whether tools were paired with appropriate recipients. Finally, in Experiment 3 we again required functional judgments as in Experiment 1, but also included in the set of stimuli pairs of objects having different function and similar functional handgrips. In all experiments, pictures displaying either functional grasping (aimed to use tools) or structural grasping (just aimed to move tools independently from their use) were presented before each stimulus pair. The results demonstrated that, in comparison with structural grasping, observing functional grasping facilitates judgments about tools' function when objects did not imply the same functional manipulation (Experiment 1), whereas worsened such judgments when objects shared functional grasp (Experiment 3). Instead, action observation did not affect judgments concerning tool-recipient associations (Experiment 2). Our findings support a task-dependent influence of motor information on high-order conceptual tasks and provide further insights into how motor and conceptual processing about tools can interact.

Impact of body posture on laterality judgement and explicit recognition tasks performed on self and others' hands.

Judgments on laterality of hand stimuli are faster and more accurate when dealing with one's own than others' hand, i.e. the self-advantage. This advantage seems to be related to activation of a sensorimotor mechanism while implicitly processing one's own hands, but not during explicit one's own hand recognition. Here, we specifically tested the influence of proprioceptive information on the self-hand advantage by manipulating participants' body posture during self and others' hand processing. In Experiment 1, right-handed healthy participants judged laterality of either self or others' hands, whereas in Experiment 2, an explicit recognition of one's own hands was required. In both experiments, the participants performed the task while holding their left or right arm flexed with their hand in direct contact with their chest ("flexed self-touch posture") or with their hand placed on a wooden smooth surface in correspondence with their chest ("flexed proprioceptive-only posture"). In an "extended control posture", both arms were extended and in contact with thighs. In Experiment 1 (hand laterality judgment), we confirmed the self-advantage and demonstrated that it was enhanced when the subjects judged left-hand stimuli at 270° orientation while keeping their left arm in the flexed proprioceptive-only posture. In Experiment 2 (explicit self-hand recognition), instead, we found an advantage for others' hand ("self-disadvantage") independently from posture manipulation. Thus, position-related proprioceptive information from left non-dominant arm can enhance sensorimotor one's own body representation selectively favouring implicit self-hands processing.