Multimodal approaches supporting the diagnosis, prognosis and investigation of neural correlates of disorders of consciousness: A systematic review.

The limits of the standard, behaviour-based clinical assessment of patients with disorders of consciousness (DoC) prompted the employment of functional neuroimaging, neurometabolic, neurophysiological and neurostimulation techniques, to detect brain-based covert markers of awareness. However, uni-modal approaches, consisting in employing just one of those techniques, are usually not sufficient to provide an exhaustive exploration of the neural underpinnings of residual awareness. This systematic review aimed at collecting the evidence from studies employing a multimodal approach, that is, combining more instruments to complement DoC diagnosis, prognosis and better investigating their neural correlates. Following the PRISMA guidelines, records from PubMed, EMBASE and Scopus were screened to select peer-review original articles in which a multi-modal approach was used for the assessment of adult patients with a diagnosis of DoC. Ninety-two observational studies and 32 case reports or case series met the inclusion criteria. Results highlighted a diagnostic and prognostic advantage of multi-modal approaches that involve electroencephalography-based (EEG-based) measurements together with neuroimaging or neurometabolic data or with neurostimulation. Multimodal assessment deepened the knowledge on the neural networks underlying consciousness, by showing correlations between the integrity of the default mode network and the different clinical diagnosis of DoC. However, except for studies using transcranial magnetic stimulation combined with electroencephalography, the integration of more than one technique in most of the cases occurs without an a priori-designed multi-modal diagnostic approach. Our review supports the feasibility and underlines the advantages of a multimodal approach for the diagnosis, prognosis and for the investigation of neural correlates of DoCs.

Unconsciousness or unresponsiveness in akinetic mutism? Insights from a multimodal longitudinal exploration.

The clinical assessment of patients with disorders of consciousness (DoC) relies on the observation of behavioural responses to standardised sensory stimulation. However, several medical comorbidities may directly impair the production of reproducible and appropriate responses, thus reducing the sensitivity of behaviour-based diagnoses. One such comorbidity is akinetic mutism (AM), a rare neurological syndrome characterised by the inability to initiate volitional motor responses, sometimes associated with clinical presentations that overlap with those of DoC. In this paper, we describe the case of a patient with large bilateral mesial frontal lesions, showing prolonged behavioural unresponsiveness and severe disorganisation of electroencephalographic (EEG) background, compatible with a vegetative state/unresponsive wakefulness syndrome (VS/UWS). By applying an unprecedented multimodal battery of advanced imaging and electrophysiology-based techniques (AIE) encompassing spontaneous EEG, evoked potentials, event-related potentials, transcranial magnetic stimulation combined with EEG and structural and functional MRI, we provide the following: (i) a demonstration of the preservation of consciousness despite unresponsiveness in the context of AM, (ii) a plausible neurophysiological explanation for behavioural unresponsiveness and its subsequent recovery during rehabilitation stay and (iii) novel insights into the relationships between DoC, AM and parkinsonism. The present case offers proof-of-principle evidence supporting the clinical utility of a multimodal hierarchical workflow that combines AIEs to detect covert signs of consciousness in unresponsive patients.

Dissociations between spontaneous electroencephalographic features and the perturbational complexity index in the minimally conscious state.

The analysis of spontaneous electroencephalogram (EEG) is a cornerstone in the assessment of patients with disorders of consciousness (DoC). Although preserved EEG patterns are highly suggestive of consciousness even in unresponsive patients, moderately or severely abnormal patterns are difficult to interpret. Indeed, growing evidence shows that consciousness can be present despite either large delta or reduced alpha activity in spontaneous EEG. Quantifying the complexity of EEG responses to direct cortical perturbations (perturbational complexity index [PCI]) may complement the observational approach and provide a reliable assessment of consciousness even when spontaneous EEG features are inconclusive. To seek empirical evidence of this hypothesis, we compared PCI with EEG spectral measures in the same population of minimally conscious state (MCS) patients (n = 40) hospitalized in rehabilitation facilities. We found a remarkable variability in spontaneous EEG features across MCS patients as compared with healthy controls: in particular, a pattern of predominant delta and highly reduced alpha power-more often observed in vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients-was found in a non-negligible number of MCS patients. Conversely, PCI values invariably fell above an externally validated empirical cutoff for consciousness in all MCS patients, consistent with the presence of clearly discernible, albeit fleeting, behavioural signs of awareness. These results confirm that, in some MCS patients, spontaneous EEG rhythms may be inconclusive about the actual capacity for consciousness and suggest that a perturbational approach can effectively compensate for this pitfall with practical implications for the individual patient's stratification and tailored rehabilitation.

Beyond alpha power: EEG spatial and spectral gradients robustly stratify disorders of consciousness.

Neurophysiological markers can overcome the limitations of behavioural assessments of Disorders of Consciousness (DoC). EEG alpha power emerged as a promising marker for DoC, although long-standing literature reported alpha power being sustained during anesthetic-induced unconsciousness, and reduced during dreaming and hallucinations. We hypothesized that EEG power suppression caused by severe anoxia could explain this conflict. Accordingly, we split DoC patients (n = 87) in postanoxic and non-postanoxic cohorts. Alpha power was suppressed only in severe postanoxia but failed to discriminate un/consciousness in other aetiologies. Furthermore, it did not generalize to an independent reference dataset (n = 65) of neurotypical, neurological, and anesthesia conditions. We then investigated EEG spatio-spectral gradients, reflecting anteriorization and slowing, as alternative markers. In non-postanoxic DoC, these features, combined in a bivariate model, reliably stratified patients and indexed consciousness, even in unresponsive patients identified as conscious by an independent neural marker (the Perturbational Complexity Index). Crucially, this model optimally generalized to the reference dataset. Overall, alpha power does not index consciousness; rather, its suppression entails diffuse cortical damage, in postanoxic patients. As an alternative, EEG spatio-spectral gradients, reflecting distinct pathophysiological mechanisms, jointly provide a robust, parsimonious, and generalizable marker of consciousness, whose clinical application may guide rehabilitation efforts.

Measuring Consciousness in the Intensive Care Unit.

Early reemergence of consciousness predicts long-term functional recovery for patients with severe brain injury. However, tools to reliably detect consciousness in the intensive care unit are lacking. Transcranial magnetic stimulation electroencephalography has the potential to detect consciousness in the intensive care unit, predict recovery, and prevent premature withdrawal of life-sustaining therapy.

Spatio-Temporal Fractal Dimension Analysis from Resting State EEG Signals in Parkinson's Disease.

Complexity analysis of electroencephalogram (EEG) signals has emerged as a valuable tool for characterizing Parkinson's disease (PD). Fractal dimension (FD) is a widely employed method for measuring the complexity of shapes with many applications in neurodegenerative disorders. Nevertheless, very little is known on the fractal characteristics of EEG in PD measured by FD. In this study we performed a spatio-temporal analysis of EEG in PD using FD in four dimensions (4DFD). We analyzed 42 resting-state EEG recordings comprising two groups: 27 PD patients without dementia and 15 healthy control subjects (HC). From the original resting-state EEG we derived the cortical activations defined by a source reconstruction at each time sample, generating point clouds in three dimensions. Then, a sliding window of one second (the fourth dimension) was used to compute the value of 4DFD by means of the box-counting algorithm. Our results showed a significantly higher value of 4DFD in the PD group (p < 0.001). Moreover, as a diagnostic classifier of PD, 4DFD obtained an area under curve value of 0.97 for a receiver operating characteristic curve analysis. These results suggest that 4DFD could be a promising method for characterizing the specific changes in the brain dynamics associated with PD.

Conventional and Investigational Approaches Leveraging Clinical EEG for Prognosis in Acute Disorders of Consciousness.

Prediction of recovery of consciousness after severe brain injury is difficult and limited by a lack of reliable, standardized biomarkers. Multiple approaches for analysis of clinical electroencephalography (EEG) that shed light on prognosis in acute severe brain injury have emerged in recent years. These approaches fall into two major categories: conventional characterization of EEG background and quantitative measurement of resting state or stimulus-induced EEG activity. Additionally, a small number of studies have associated the presence of electrophysiologic sleep features with prognosis in the acute phase of severe brain injury. In this review, we focus on approaches for the analysis of clinical EEG that have prognostic significance and that could be readily implemented with minimal additional equipment in clinical settings, such as intensive care and intensive rehabilitation units, for patients with acute disorders of consciousness.

Letter to the editor: COVID in patients with brain injury with a disorder of consciousness: a pathogenetic theory.

We recently published in this journal (Caronni and colleagues, Brain Injury, 2021-04-16) the first description of the spread of the SARS-CoV-2 infection in a cohort of brain injured patients with a disorder of consciousness (DOC). Surprisingly enough we showed that, in these patients, the COVID was moderate and did not result in fatalities. The pathogenesis of the COVID is characterized by the profound dysregulation of the immune system. To explain our findings, we speculated that the immunosuppression due to the brain injury could be protective against the development of the COVID in patients with DOC. More recently, a second group of authors (Marino and colleagues, PLoSOne, 2021-06-30) described the course of the COVID in an independent cohort of patients with DOC. Since our results were quite unexpected, we have been very comforted by the data reported by Marino and colleagues. Moreover, these data also offer a unique opportunity to further evaluate our theory regarding the COVID pathogenesis in patients with DOC. In the current Letter to the Editor it is shown that the independent data presented by Marino and colleagues do support our theory. Waiting for larger cohorts to further test it (and in case falsify it), our interpretation seems to remain valid.

Clinical course of SARS-CoV-2 infection in patients with severe acquired brain injury and a disorder of consciousness: an observational study.

Purpose: SARS-CoV-2 infection can cause the coronavirus disease (COVID), ranging from flu-like symptoms to interstitial pneumonia. Mortality is high in COVID pneumonia and it is the highest among the frailest. COVID could be particularly serious in patients with severe acquired brain injury (SABI), such as those with a disorder of consciousness. We here describe a cohort of patients with a disorder of consciousness exposed to SARS-CoV-2 early after their SABI.Materials and methods: The full cohort of 11 patients with SABI hospitalized in March 2020 in the IRCCS Fondazione Don Gnocchi rehabilitation (Milan, Italy) was recruited. Participants received SARS-CoV-2 testing and different clinical and laboratory data were collected.Results: Six patients contracted SARS-CoV-2 and four of them developed the COVID. Of these, one patient had ground-glass opacities on the chest CT scan, while the remaining three developed consolidations. No patient died and the overall respiratory involvement was mild, requiring in the worst cases low-flow oxygen.Conclusions: Here we report the clinical course of a cohort of patients with SABI exposed to SARS-CoV-2. The infection spread among patients and caused COVID in some of them. Unexpectedly, COVID was moderate, caused at most mild respiratory distress and did not result in fatalities.

Stratification of unresponsive patients by an independently validated index of brain complexity.

OBJECTIVE: Validating objective, brain-based indices of consciousness in behaviorally unresponsive patients represents a challenge due to the impossibility of obtaining independent evidence through subjective reports. Here we address this problem by first validating a promising metric of consciousness-the Perturbational Complexity Index (PCI)-in a benchmark population who could confirm the presence or absence of consciousness through subjective reports, and then applying the same index to patients with disorders of consciousness (DOCs). METHODS: The benchmark population encompassed 150 healthy controls and communicative brain-injured subjects in various states of conscious wakefulness, disconnected consciousness, and unconsciousness. Receiver operating characteristic curve analysis was performed to define an optimal cutoff for discriminating between the conscious and unconscious conditions. This cutoff was then applied to a cohort of noncommunicative DOC patients (38 in a minimally conscious state [MCS] and 43 in a vegetative state [VS]). RESULTS: We found an empirical cutoff that discriminated with 100% sensitivity and specificity between the conscious and the unconscious conditions in the benchmark population. This cutoff resulted in a sensitivity of 94.7% in detecting MCS and allowed the identification of a number of unresponsive VS patients (9 of 43) with high values of PCI, overlapping with the distribution of the benchmark conscious condition. INTERPRETATION: Given its high sensitivity and specificity in the benchmark and MCS population, PCI offers a reliable, independently validated stratification of unresponsive patients that has important physiopathological and therapeutic implications. In particular, the high-PCI subgroup of VS patients may retain a capacity for consciousness that is not expressed in behavior. Ann Neurol 2016;80:718-729.

Italian translation and cultural adaptation of the Agitated Behavior Scale (ABS-I) in patients with acquired brain injuries.

OBJECTIVE: The objective of this study was to produce a cross-cultural adaptation in Italian of the Agitated Behavior Scale (ABS), originally developed in English, as the first of two stages that also include cross-cultural validation and allow a clinical scale to be used in the proper setting such as rehabilitation units. METHODS: In order to adapt the ABS scale to a different cultural environment, five consecutive steps were performed: (1) forward translations (n = 8), (2) synthesis of the 8 forward translations to obtain a first shared italian version (ABS_I_trial), (3) back translations (n = 3), (4) creation of an expert committee to evaluate forward and back translations and finally (5) the cognitive debriefing. RESULTS: After the five steps, including forward translations and back translations, the process of committee verification and judgement and the evaluative step of cognitive debriefing, high comprehensibility of all items was found, resulting in an Italian translation version of ABS suitable for application in a clinical setting. CONCLUSION: ABS translation was produced by means of a standardized procedure aimed at minimizing cross-cultural gaps. The expert committee evaluated the version produced as highly understandable in Italian. Further steps, such as the subsequent validation of its psychometric properties, are needed to employ this translation in a clinical setting.

Efficacy of lacosamide on seizures and myoclonus in a patient with epilepsia partialis continua.

A 39-year-old male with epilepsia partialis continua, refractory to first- and second-line antiepileptic drugs, is described. Lacosamide produced a progressive antiepileptic effect on Jacksonian motor seizures and subsequently on positive myoclonus, which developed into negative myoclonus before complete resolution. Our report confirms the efficacy of lacosamide on focal motor refractory status epilepticus and documents a unique effect of lacosamide on seizure semiology.

Informal Caregivers of Patients with Disorders of Consciousness: a Qualitative Study of Communication Experiences and Information Needs with Physicians.

Due to improvements in medicine, the figures of patients with disorders of consciousness (DoC) are increasing. Diagnostics of DoC and prognostication of rehabilitation outcome is challenging but necessary to evaluate recovery potential and to decide on treatment options. Such decisions should be made by doctors and patients' surrogates based on medico-ethical principles. Meeting information needs and communicating effectively with caregivers as the patients´ most common surrogate-decision makers is crucial, and challenging when novel tech-nologies are introduced. This qualitative study aims to explore information needs of informal DoC caregivers, how they manage the obtained information and their perceptions and experiences with caregiver-physician communication in facilities that implemented innovative neurodiagnostics studies. In 2021, we conducted semi-structured interviews with nine caregivers of clinically stable DoC patients in two rehabilitation centers in Italy and Germany. Participants were selected based on consecutive purposeful sampling. Caregivers were recruited at the facilities after written informed consent. All interviews were recorded, transcribed verbatim and translated. For analysis, we used reflexive thematic analysis according to Braun & Clarke (2006). Caregivers experienced the conversations emotionally, generally based on the value of the information provided. They reported to seek positive information, comfort and empathy with-in the communication of results of examinations. They needed detailed information to gain a deep understanding and a clear picture of their loved-one's condition. The results suggest a mismatch between the perspectives of caregivers and the perspectives of medical profession-als, and stress the need for more elaborate approaches to the communication of results of neu-rodiagnostics studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s12152-022-09503-0.

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.

Detecting the Potential for Consciousness in Unresponsive Patients Using the Perturbational Complexity Index.

The difficulties of behavioral evaluation of prolonged disorders of consciousness (DOC) motivate the development of brain-based diagnostic approaches. The perturbational complexity index (PCI), which measures the complexity of electroencephalographic (EEG) responses to transcranial magnetic stimulation (TMS), showed a remarkable sensitivity in detecting minimal signs of consciousness in previous studies. Here, we tested the reliability of PCI in an independently collected sample of 24 severely brain-injured patients, including 11 unresponsive wakefulness syndrome (UWS), 12 minimally conscious state (MCS) patients, and 1 emergence from MCS patient. We found that the individual maximum PCI value across stimulation sites fell within the consciousness range (i.e., was higher than PCI*, which is an empirical cutoff previously validated on a benchmark population) in 11 MCS patients, yielding a sensitivity of 92% that surpassed qualitative evaluation of resting EEG. Most UWS patients (n = 7, 64%) showed a slow and stereotypical TMS-EEG response, associated with low-complexity PCI values (i.e., ≤PCI*). Four UWS patients (36%) provided high-complexity PCI values, which might suggest a covert capacity for consciousness. In conclusion, this study successfully replicated the performance of PCI in discriminating between UWS and MCS patients, further motivating the application of TMS-EEG in the workflow of DOC evaluation.

Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage.

BACKGROUND: Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). OBJECTIVE: We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. METHODS: In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. RESULTS: We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. CONCLUSIONS: These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.

Cardiac autonomic responses to nociceptive stimuli in patients with chronic disorders of consciousness.

OBJECTIVES: Patients with chronic disorders of consciousness (DOC) may show alterations of autonomic function; however, in this clinical population, no data are available on the specific effects of nociceptive stimuli on cardiac autonomic control. Thus, we aimed at investigating the effects of a noxious stimulation on heart rate variability (HRV) in a population of patients with chronic DOC, taking into account different states of consciousness (vegetative state/unresponsive wakefulness syndrome, VS/UWS and minimally conscious state, MCS). METHODS: We enrolled twenty-four DOC patients (VS/UWS, n = 12 and MCS, n = 12). ECG and respiration were recorded during baseline, immediately after the nociceptive stimulus and, finally, during the recovery period. Linear and nonlinear HRV measures were used to evaluate the cardiac autonomic control. RESULTS: In DOC patients, nonlinear HRV analysis showed that nociceptive stimuli are able to elicit a change of autonomic function characterized by an increased sympathetic and a reduced vagal modulation. A significant reduction of autonomic complexity has also been detected. More interestingly, VS/UWS patients showed a less complex dynamics compared to MCS patients. CONCLUSIONS: Cardiac autonomic responses are able to significantly differentiate the autonomic function between VS/UWS and MCS patients. SIGNIFICANCE: Nonlinear HRV analysis may represent a useful tool to characterize the cardiac autonomic responses to nociceptive stimuli in a chronic DOC population.