The Prognostic Role of Candidate Serum Biomarkers in the Post-Acute and Chronic Phases of Disorder of Consciousness: A Preliminary Study.

INTRODUCTION: Serum biomarkers, such as Neurofilament Light (NF-L), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase (UCH-L1), and Total-tau (T-Tau) have been proposed for outcome prediction in the acute phase of severe traumatic brain injury, but they have been less investigated in patients with prolonged DoC (p-DoC). METHODS: We enrolled 25 p-DoC patients according to the Coma Recovery Scale-Revised (CRS-R). We identified different time points: injury onset (t0), first blood sampling at admission in Neurorehabilitation (t1), and second blood sampling at discharge (t2). Patients were split into improved (improved level of consciousness from t1 to t2) and not-improved (unchanged or worsened level of consciousness from t1 to t2). RESULTS: All biomarker levels decreased over time, even though each biomarker reveals typical features. Serum GFAP showed a weak correlation between t1 and t2 (p = 0.001), while no correlation was observed for serum NF-L (p = 0.955), UCH-L1 (p = 0.693), and T-Tau (p = 0.535) between t1 and t2. Improved patients showed a significant decrease in the level of NF-L (p = 0.0001), UCH-L1 (p = 0.001), and T-Tau (p = 0.002), but not for serum GFAP (p = 0.283). No significant statistical differences were observed in the not-improved group. CONCLUSIONS: A significant correlation was found between the level of consciousness improvement and decreased NF-L, UCH-L1, and T-Tau levels. Future studies on the association of serum biomarkers with neurophysiological and neuroimaging prognostic indicators are recommended.

The Possible Role of Apathy on Conflict Monitoring: Preliminary Findings of a Behavioral Study on Severe Acquired Brain Injury Patients Using Flanker Tasks.

The diagnosis of apathy, one of the most common behavioral changes after acquired brain injury (ABI), is important for improving clinical understanding and treatment of persons with ABI. The main aim of this study was to determine the possible role of apathy in conflict monitoring, by using choice reaction time tasks. Methods: We examined behavioral responses of conflict monitoring during three different flanker tasks in 10 severe ABI patients with or without diagnosis of apathy (3 M, mean age = 56.60; 3 M, mean age ± SD = 58.60, respectively), and 15 healthy controls (9 M, mean age = 54.46) Reaction times (RTs), accuracy, and global index of performance (GIP) were analyzed for each task. Results: Only apathetic ABI patients showed a significant difference from healthy subjects (p-value ≤ 0.001), while the performance of patients without apathy was not significantly different from that of healthy controls (p-value = 0.351). Healthy participants had higher accuracy in comparison to both ABI patients with (p < 0.001) and without (p-value = 0.038) apathy, whilst slower RTs were shown by ABI patients without apathy in comparison to both healthy subjects (p-value = 0.045) and apathetic ABI patients (p-value = 0.022). Only patients with apathy exhibited a significantly higher number of missing trials (p-value = 0.001). Conclusions: Our results may suggest a potential link between apathy following severe ABI and conflict monitoring processes, even though further investigations with larger sample size are needed.

EEG-based Brain-Computer Interfaces for people with Disorders of Consciousness: Features and applications. A systematic review.

Background: Disorders of Consciousness (DoC) are clinical conditions following a severe acquired brain injury (ABI) characterized by absent or reduced awareness, known as coma, Vegetative State (VS)/Unresponsive Wakefulness Syndrome (VS/UWS), and Minimally Conscious State (MCS). Misdiagnosis rate between VS/UWS and MCS is attested around 40% due to the clinical and behavioral fluctuations of the patients during bedside consciousness assessments. Given the large body of evidence that some patients with DoC possess "covert" awareness, revealed by neuroimaging and neurophysiological techniques, they are candidates for intervention with brain-computer interfaces (BCIs). Objectives: The aims of the present work are (i) to describe the characteristics of BCI systems based on electroencephalography (EEG) performed on DoC patients, in terms of control signals adopted to control the system, characteristics of the paradigm implemented, classification algorithms and applications (ii) to evaluate the performance of DoC patients with BCI. Methods: The search was conducted on Pubmed, Web of Science, Scopus and Google Scholar. The PRISMA guidelines were followed in order to collect papers published in english, testing a BCI and including at least one DoC patient. Results: Among the 527 papers identified with the first run of the search, 27 papers were included in the systematic review. Characteristics of the sample of participants, behavioral assessment, control signals employed to control the BCI, the classification algorithms, the characteristics of the paradigm, the applications and performance of BCI were the data extracted from the study. Control signals employed to operate the BCI were: P300 (N = 19), P300 and Steady-State Visual Evoked Potentials (SSVEP; hybrid system, N = 4), sensorimotor rhythms (SMRs; N = 5) and brain rhythms elicited by an emotional task (N = 1), while assessment, communication, prognosis, and rehabilitation were the possible applications of BCI in DoC patients. Conclusion: Despite the BCI is a promising tool in the management of DoC patients, supporting diagnosis and prognosis evaluation, results are still preliminary, and no definitive conclusions may be drawn; even though neurophysiological methods, such as BCI, are more sensitive to covert cognition, it is suggested to adopt a multimodal approach and a repeated assessment strategy.

Physical Therapy Exercises for Sleep Disorders in a Rehabilitation Setting for Neurological Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Sleep occupies one-third of human life and is essential for health and for emotional, physical, and cognitive well-being. Poor or insufficient sleep is associated with a wide range of dysfunctions that involve different body systems, such as the endocrine, metabolic, and immune systems, thus compromising the higher cortical functions, cognitive performance, mood, and post-physical activity recovery. The present systematic review and meta-analysis aimed to explore the effectiveness of physical therapy exercises on sleep disorders in patients with neurological disorders. Our systematic review identified 10 articles that investigated the effects of physical therapy on sleep disorders in patients with neurological disorders, 6 of which were included in the meta-analysis. Results suggest that physical therapy exercises are a safe and useful strategy for managing sleep disorders in neurorehabilitation.

Predicting Outcome of Acquired Brain Injury by the Evolution of Paroxysmal Sympathetic Hyperactivity Signs.

In this multi-center study, we provide a systematic evaluation of the clinical variability associated with paroxysmal sympathetic hyperactivity (PSH) in patients with acquired brain injury (ABI) to determine how these signs can impact outcomes. A total of 156 ABI patients with a disorder of consciousness (DoC) were admitted to neurorehabilitation subacute units (intensive rehabilitation unit; IRU) and evaluated at baseline (T0), after 4 months from event (T1), and at discharge (T2). The outcome measure was the Glasgow Outcome Scale-Extended, whereas age, sex, etiology, Coma Recovery Scale-Revised (CRS-r), Rancho Los Amigos Scale (RLAS), Early Rehabilitation Barthel Index (ERBI), PSH-Assessment Measure (PSH-AM) scores and other clinical features were considered as predictive factors. A machine learning (ML) approach was used to identify the best predictive model of clinical outcomes. The etiology was predominantly vascular (50.8%), followed by traumatic (36.2%). At admission, prevalence of PSH was 31.3%, which decreased to 16.6% and 4.4% at T1 and T2, respectively. At T2, 2.8% were dead and 61.1% had a full recovery of consciousness, whereas 36.1% remained in VS or MCS. A support vector machine (SVM)-based ML approach provides the best model with 82% accuracy in predicting outcomes. Analysis of variable importance shows that the most important clinical factors influencing the outcome are the PSH-AM scores measured at T0 and T1, together with neurological diagnosis, CRS-r, and RLAS scores measured at T0. This joint multi-center effort provides a comprehensive picture of the clinical impact of PSH signs in ABI patients, demonstrating its predictive value in comparison with other well-known clinical measurements.

Pain and Evil: From Local Nociception to Misery Following Social Harm.

Experiencing pain, especially when chronic, is an excruciating condition that should be regarded as a syndrome, if not a disease. People suffering from chronic pain tend to develop psychological discomfort mostly due to lack of acceptance, disbelief, blame. The complexity of pain pathophysiology, plus a wide range of negative psychosocial factors, leads to a more complex suffering that deserves attention and multidisciplinary treatments. The possibility that chronic pain may occur following physical aggression, torture, or persecution raises the issue of evil as a major contributor to pain in its worst representation - when individuals or groups are attacked based on racial, social, gender, religious, political, or other grounds. To explore the complex issue of chronic pain following physical or psychological harm, and to underscore the need for a multidisciplinary approach to reduce the burden of chronic pain, we discuss the biological mechanisms underlying pain state. We seek to clarify those factors leading to pain chronification, as well as personal and social attitudes that confound patients with chronic pain. The importance of family and social environment is also investigated, as well as personality traits of chronic pain patients that may further hamper successful treatment. The presence of chronic pain, modulated by, for example, acceptance of being a victim of premeditated physical and social violence, makes the issue more difficult to comprehend.

Author Correction: Pain perception during social interactions is modulated by self-related and moral contextual cues.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pain perception during social interactions is modulated by self-related and moral contextual cues.

Despite the growing interest on the effect of the social context on pain, whether and how different facets of interpersonal interactions modulate pain are still unclear. We tested whether personal (i.e., convenient for the self), moral (i.e., equitability of the transaction) or social (i.e., positive vs. negative feedback from others) valence of an interpersonal interaction differentially affects pain and the perceived fairness. Thirty-two healthy participants played the role of Receivers in a Dictator Game, where a player, the Dictator, determined how to divide a payoff between her/himself and the other player, the Receiver. We manipulated the payoff (pain vs. money), the personal valence (favorable vs. unfavorable offer to participants), the moral valence of the offer (from very iniquitous to equitable), and social valence of the Dictator (social acceptance vs. rejection). Moral and personal valence differentially modulated pain. Lower pain was elicited by iniquity, but also by favorable offers. Moreover, unfavorable offers in the economic game were rated as more unfair, whereas only very iniquitous offers elicited such ratings in the pain game, suggesting that participants valued when Dictators endured extra pain for their benefit. Together, we show that the valence of a social interaction at different levels can independently modulate pain and fairness perception.

A new tool to assess responsiveness in disorders of consciousness (DoC): a preliminary study on the Brief Post-Coma Scale (BPCS).

INTRODUCTION: The Brief Post-Coma Scale (BPCS) is an easy diagnostic tool for individuals with disorders of consciousness (DoC), in a reduced version from a previously Post-Coma Scale, that could distinguish patients in the minimally conscious state (MCS) from those in unresponsive wakefulness syndrome (UWS), formerly defined as vegetative state (VS). OBJECTIVE: Aim of the study was to assess the diagnostic validity of the BPCS in comparison with the Coma Recovery Scale-Revised (CRS-R), in its Italian validated version, the Disability Rating Scale (DRS), the Level of Cognitive Functioning (LCF), and the Glasgow Outcome Scale (GOS). METHODS: In an Italian multicenter study on 545 patients with DoC, 36 post-acute rehabilitation wards, 32 long-term care centers, and 2 family associations participated to data collection. RESULTS: Statistically significant correlations were found between the BPCS and the other clinical scales: R = 0.586 (p < 0.001) with LCF, R = - 0.566 (p < 0.001) with DRS, R = 0.622 (p < 0.001) with CRS-R. The BPCS scores resulted significantly correlated with the time from acute event (R = 0.117, p = 0.006). Patients with GOS score 2 had mean BPCS of 1.84 ± 1.19, whereas those with GOS 3 had significantly higher scores 3.88 ± 1.71 (p < 0.001). Similarly, in patients with vegetative state/UWS (VS/UWS), the mean BPSC score was 1.71 ± 1.09, significantly lower (p < 0.001) than that of patients with minimally conscious state (BPCS = 3.83 ± 1.29). Finally, the agreement of the BPCS and clinical diagnosis was of 84.4%, with an odds ratio OR = 3.781 (95% CI = 3.026-4.725, p < 0.001). CONCLUSIONS: The BPCS has demonstrated statistically significant correlations with the most commonly used scales in persons with DoC.

Assessing and treating primary headaches and cranio-facial pain in patients undergoing rehabilitation for neurological diseases.

BACKGROUND: Pain is a very common condition in patient undergoing rehabilitation for neurological disease; however the presence of primary headaches and other cranio-facial pains, particularly when they are actually or apparently independent from the disability for which patient is undergoing rehabilitation, is often neglected. Diagnostic and therapeutic international and national guidelines, as well as tools for the subjective measure of head pain are available and should also be applied in the neurorehabilitation setting. This calls for searching the presence of head pain, independently from the rehabilitation needs, since pain, either episodic or chronic, interferes with patient performance by affecting physical and emotional status. Pain may also interfere with sleep and therefore hamper recovery. METHODS: In our role of task force of the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN), we have elaborated specific recommendations for diagnosing and treating head pains in patients undergoing rehabilitation for neurological diseases. RESULTS AND CONCLUSION: In this narrative review, we describe the available literature that has been evaluated in order to define the recommendations and outline the needs of epidemiological studies concerning headache and other cranio-facial pain in neurorehabilitation.

Analysis of Italian regulations on pathways of care for patients in a vegetative or minimally conscious state.

Different rehabilitation models for persons diagnosed with disorders of consciousness have been proposed in Europe during the last decade. In Italy, the Ministry of Health has defined a national healthcare model, although, to date, there is a lack of information on how this has been implemented at regional level. The INCARICO project collected information on different regional regulations, analysing ethical aspects and mapping care facilities (numbers of beds and medical units) in eleven regional territories. The researchers found a total of 106 laws; differences emerged both between regions and versus the national model, showing that patients with the same diagnosis may follow different pathways of care. An ongoing cultural shift from a treatment-oriented medical approach towards a care-oriented integrated biopsychosocial approach was found in all the welfare and healthcare systems analysed. Future studies are needed to explore the relationship between healthcare systems and the quality of services provided.

Care pathways models and clinical outcomes in Disorders of consciousness.

OBJECTIVE: Patients with Disorders of consciousness, are persons with extremely low functioning levels and represent a challenge for health care systems due to their high needs of facilitating environmental factors. Despite a common Italian health care pathway for these patients, no studies have analyzed information on how each region have implemented it in its welfare system correlating data with patients' clinical outcomes. MATERIALS AND METHODS: A multicenter observational pilot study was realized. Clinicians collected data on the care pathways of patients with Disorder of consciousness by asking 90 patients' caregivers to complete an ad hoc questionnaire through a structured phone interview. Questionnaire consisted of three sections: sociodemographic data, description of the care pathway done by the patient, and caregiver evaluation of health services and information received. RESULTS: Seventy-three patients were analyzed. Length of hospital stay was different across the health care models and it was associated with improvement in clinical diagnosis. In long-term care units, the diagnosis at admission and the number of caregivers available for each patient (median value = 3) showed an indirect relationship with worsening probability in clinical outcome. Caregivers reported that communication with professionals (42%) and the answer to the need of information were the most critical points in the acute phase, whereas presence of Non-Governmental Organizations (25%) and availability of psychologists for caregivers (21%) were often missing during long-term care. The 65% of caregivers reported they did not know the UN Convention on the Rights of Persons with Disabilities. CONCLUSION: This study highlights relevant differences in analyzed models, despite a recommended national pathway of care. Future public health considerations and actions are needed to guarantee equity and standardization of the care process in all European countries.

Effects of Osteopathic Manipulative Therapy on Pain and Mood Disorders in Patients With High-Frequency Migraine.

CONTEXT: The substantial functional impairment associated with migraine has both physical and emotional ramifications. Mood disorders are often comorbid in patients with migraine and are known to adversely affect migraine activity. OBJECTIVES: To explore the effects of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) on pain and mood disorders in patients with high-frequency migraine. METHODS: Retrospective review of the medical records of patients with high-frequency migraine who were treated with OMTh at the Headache Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia from 2011 to 2015. Clinical assessments were made using the Headache Disability Inventory (HDI), the Headache Impact Test (HIT-6), the Hamilton Depression Rating Scale (HDRS), and the State-Trait Anxiety Inventory (STAI) forms X-1 and X-2. RESULTS: Medical records of 11 patients (6 women; mean age, 47.5 [7.8] years) with a diagnosis of high-frequency migraine who participated in an OMTh program met the inclusion criteria and were included in the study. When the questionnaire scores obtained at the first visit (T0) and after 4 OMTh sessions (T1) were compared, significant improvement in scores were observed on STAI X-2 (T0: 43.18 [2.47]; T1: 39.45 [2.52]; P<.05), HIT-6 (T0: 63 [2.20]; T1: 56.27 [2.24]; P<.05), and HDI (T0: 58.72 [6.75]; T1: 45.09 [7.01]; P<.05). CONCLUSION: This preliminary study revealed that patients with high-frequency migraine and comorbid mood disorders showed significant improvement after four 45-minute OMTh sessions. Further investigation into the effects of OMTh on pain and mood disorders in patients with high-frequency migraine is needed.

Quality of life after brain injury (QOLIBRI): Italian validation of the proxy version.

To validate the proxy version of the Quality of Life after Brain Injury (QOLIBRI) questionnaire to utilize caregivers for comparison and to evaluate the correspondence between patients' self-perceived and caregivers' perception of patients' Health-Related Quality of Life (HRQoL). Ninety-two patients with severe TBI and their main caregivers were enrolled. Patients' and caregivers' HRQoL was assessed by the Patient-QOLIBRI (Pt-QOLIBRI) and the Proxy-QOLIBRI (Pro-QOLIBRI), respectively. The Pro-QOLIBRI is a modified version of the QOLIBRI to investigate caregivers' perception of patients' HRQoL (Pro-QOLIBRIpatient-centered), and their degree of satisfaction and botheredness (Pro-QOLIBRIcaregiver centered). The patients' disability and their social reintegration was investigated by means of Glasgow Outcome Scale Extended and Community Integration Questionnaire. Pro-QOLIBRI has good internal consistency and homogeneity. There was also positive correlation between the level of satisfaction measured by Pro-QOLIBRI but not by Pt-QOLIBRI, and the disability severity and social integration of the patients. The comparison between the Pt-QOLIBRI and Pro-QOLIBRI confirmed the usefulness of the Pro-QOLIBRI, especially the caregiver-centered version, to predict the social reintegration of survivors. To our knowledge this is the first study that correlates the HRQoL of survivors, as self-perceived and as perceived by the caregivers with social reintegration.

Quality of life in persons after traumatic brain injury as self-perceived and as perceived by the caregivers.

The primary aim of the study was to adopt QOLIBRI (quality of life after brain injury) questionnaire in a proxy version (Q-Pro), i.e., to use caregivers for comparison and to evaluate whether TBI patients' judgment corresponds to that of their caregivers since the possible self-awareness deficit of the persons with TBI. A preliminary sample of 19 outpatients with TBI and their proxies was first evaluated with the Patient Competency Rating Scale to assess patients' self-awareness; then they were evaluated with the QOLIBRI Patient version (Q-Pt) and a patient-centered version of the Q-Pro. Subsequently, 55 patients and their caregivers were evaluated using the patient-centered and the caregiver-centered Q-Pro versions. Q-Pt for assessing Quality of Life (QoL) after TBI, as patients' subjective perspective and Q-Pro to assess the QoL of patients as perceived by the caregivers. The majority of patients (62.2%) showed better self-perception of QoL than their proxies; however, patients with low self-awareness were less satisfied than patients with adequate self-awareness. Low self-awareness does not impair the ability of patients with TBI to report on satisfaction with QoL as self-perceived.

Health-related quality of life after traumatic brain injury: Italian validation of the QOLIBRI.

The QOLIBRI (Quality of Life after Brain Injury) is a new international health-related quality of life (HRQoL) instrument developed for assessing the consequences of traumatic brain injury (TBI). We report the results of the Italian validation of the QOLIBRI. A total of 147 participants with TBI who had previously been discharged from the Santa Lucia Foundation rehabilitation hospital were recruited to investigate the concurrent validity of the Italian version of the QOLIBRI and to compare this instrument with several functional and cognitive-behavioral scales, taking into account various clinical parameters. The QOLIBRI met the standard criteria for internal consistency, homogeneity and test-retest reliability. The results suggest that it is very sensitive in relation to outcome as measured by the Extended Glasgow Outcome Scale (GOS-E) and other instruments for functional assessment of disability, emotions and subjective health status, including the Hospital Anxiety and Depression Scale and the Short-Form 36. The QOLIBRI avoids some of the limitations of traditional scales for quantifying residual functional capaci-Health-related quality of life after traumatic brain injury: Italian validation of the QOLIBRI, such as the Glasgow Outcome Scale and the GOS-E, and may contribute to the achievement of better quality-controlled care, medical decision-making, rehabilitation planning, and measurement of well-being and HRQoL from the patient's perspective. However, a longitudinal study is needed to assess the responsiveness of the QOLIBRI to changes over time.

Increased levels of serum IL-18 are associated with the long-term outcome of severe traumatic brain injury.

OBJECTIVE: A long-lasting neuroinflammatory cascade may lead to the progression of brain damage, favoring neurodegeneration and cognitive impairment in patients with traumatic brain injury (TBI), but the potential mechanisms underlying this sequence of events remain elusive. Here we aimed to evaluate the impact of interleukin (IL)-18, a proinflammatory cytokine elevated in post-acute head injury and associated with neurodegeneration, on the long-term outcome of patients with chronic TBI. METHODS: The serum content of IL-18 was evaluated in 16 patients with severe TBI, during their rehabilitation phase, and in a matched group of 16 healthy controls. The disability of the enrolled patients was evaluated by means of the Glasgow Outcome Scale, Levels of Cognitive Functioning, and the Disability Rating Scale. RESULTS: The circulating levels of IL-18 were significantly increased in chronic TBI patients, as compared to healthy subjects, and correlated with the patients' cognitive impairment and disability severity. CONCLUSIONS: IL-18 may contribute to the long-term outcome and neurodegeneration in TBI patients. Even though further studies are needed to understand the molecular mechanisms underlying the effects of IL-18 on TBI progression and its associated drop in cognitive function, a possible role of this cytokine as a therapeutic target in TBI can be envisaged.

Increased levels of serum MAP-2 at 6-months correlate with improved outcome in survivors of severe traumatic brain injury.

OBJECTIVE: To evaluate microtubule-associated proteins (MAP-2), a dendritic marker of both acute damage and chronic neuronal regeneration after injury, in serum of survivors after severe TBI and examine the association with long-term outcome. METHODS: Serum concentrations of MAP-2 were evaluated in 16 patients with severe TBI (Glasgow Coma Scale score [GCS] ≤ 8) 6 months post-injury and in 16 controls. Physical and cognitive outcomes were assessed, using the Glasgow Outcome Scale Extended (GOSE) and Levels of Cognitive Functioning Scale (LCFS), respectively. RESULTS: Severe TBI patients had significantly higher serum MAP-2 concentrations than normal controls with no history of TBI (p = 0.008) at 6 months post-injury. MAP-2 levels correlated with the GOSE (r = 0.58, p = 0.02) and LCFS (r = 0.65, p = 0.007) at month 6. Significantly lower serum levels of MAP-2 were observed in patients in a vegetative state (VS) compared to non-VS patients (p < 0.05). A trend tracking the level of consciousness was observed. CONCLUSIONS: Severe TBI results in a chronic release of MAP-2 into the peripheral circulation in patients with higher levels of consciousness, suggesting that remodelling of synaptic junctions and neuroplasticity processes occur several months after injury. The data indicate MAP-2 as a potential marker for emergence to higher levels of cognitive function.