A neurophysiological profiling of the heartbeat-evoked potential in severe acquired brain injuries: A focus on unconsciousness.

Unconsciousness in severe acquired brain injury (sABI) patients occurs with different cognitive and neural profiles. Perturbational approaches, which enable the estimation of proxies for brain reorganization, have added a new avenue for investigating the non-behavioural diagnosis of consciousness. In this prospective observational study, we conducted a comparative analysis of the topological patterns of heartbeat-evoked potentials (HEP) between patients experiencing a prolonged disorder of consciousness (pDoC) and patients emerging from a minimally consciousness state (eMCS). A total of 219 sABI patients were enrolled, each undergoing a synchronous EEG-ECG resting-state recording, together with a standardized consciousness diagnosis. A number of graph metrics were computed before/after the HEP (Before/After) using the R-peak on the ECG signal. The peak value of the global field power of the HEP was found to be significantly higher in eMCS patients with no difference in latency. Power spectrum was not able to discriminate consciousness neither Before nor After. Node assortativity and global efficiency were found to vary with different trends at unconsciousness. Lastly, the Perturbational Complexity Index of the HEP was found to be significantly higher in eMCS patients compared with pDoC. Given that cortical elaboration of peripheral inputs may serve as a non-behavioural determinant of consciousness, we have devised a low-cost and translatable technique capable of estimating causal proxies of brain functionality with an endogenous, non-invasive stimulus. Thus, we present an effective means to enhance consciousness assessment by incorporating the interaction between the autonomic nervous system (ANS) and central nervous system (CNS) into the loop.

Implications of the Consciousness State on Decannulation in Patients With a Prolonged Disorder of Consciousness.

OBJECTIVE: To prospectively investigate the evolution of the consciousness state and the cannula-weaning progression in patients with prolonged disorders of consciousness. DESIGN: Nonconcurrent cohort study. SETTING: A rehabilitation unit. PARTICIPANTS: Adult patients (N=144) with prolonged disorders of consciousness after a severe acquired brain injury admitted between June 2020 and September 2022. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Consciousness state was assessed by repeated Coma Recovery Scale-Revised (CRS-R) questionnaire administration at admission and weekly afterward. The dates of the first improvement of consciousness state and the achievement of decannulation were recorded. Decannulation followed an internal protocol of multiprofessional rehabilitation. RESULTS: One hundred forty-four patients were included: age, 69 years; 64 (44.4%) with hemorrhagic etiology; time post onset, 40 days, CRS-R score at admission, 9, median length of stay, 90 days. Seventy-three (50.7%) patients were decannulated. They showed a significantly higher CRS-R (P<.001) and states of consciousness (P<.001) at admission, at the first improvement of the consciousness state (P=.003), and at discharge (P<.001); a lower severity in the Cumulative Illness Rating Scale at admission (P=.01); and a lower rate of pulmonary infections with recurrence (P=.021), compared with nondecannulated patients. Almost all decannulated patients (97.3%) improved their consciousness before decannulation. Consciousness states at decannulation were as follows: unresponsive wakefulness syndrome, 0 (0%); minimally conscious state (MCS) minus, 4 (5.5%); MCS plus, 7 (9.6%); and emergence from MCS, 62 (84.9%). Kaplan-Meier analysis showed a significant divergence between the curves with a higher probability of decannulation in patients who improved consciousness (P<.001). CONCLUSIONS: This study showed that the presence of signs of consciousness, even subtle, is a necessary condition for decannulation, suggesting that consciousness may influence some of the components implied in the decannulation process.

PRedicting the EVolution of SubjectIvE Cognitive Decline to Alzheimer's Disease With machine learning: the PREVIEW study protocol.

BACKGROUND: As disease-modifying therapies (DMTs) for Alzheimer's disease (AD) are becoming a reality, there is an urgent need to select cost-effective tools that can accurately identify patients in the earliest stages of the disease. Subjective Cognitive Decline (SCD) is a condition in which individuals complain of cognitive decline with normal performances on neuropsychological evaluation. Many studies demonstrated a higher prevalence of Alzheimer's pathology in patients diagnosed with SCD as compared to the general population. Consequently, SCD was suggested as an early symptomatic phase of AD. We will describe the study protocol of a prospective cohort study (PREVIEW) that aim to identify features derived from easily accessible, cost-effective and non-invasive assessment to accurately detect SCD patients who will progress to AD dementia. METHODS: We will include patients who self-referred to our memory clinic and are diagnosed with SCD. Participants will undergo: clinical, neurologic and neuropsychological examination, estimation of cognitive reserve and depression, evaluation of personality traits, APOE and BDNF genotyping, electroencephalography and event-related potential recording, lumbar puncture for measurement of Aß42, t-tau, and p-tau concentration and Aß42/Aß40 ratio. Recruited patients will have follow-up neuropsychological examinations every two years. Collected data will be used to train a machine learning algorithm to define the risk of being carriers of AD and progress to dementia in patients with SCD. DISCUSSION: This is the first study to investigate the application of machine learning to predict AD in patients with SCD. Since all the features we will consider can be derived from non-invasive and easily accessible assessments, our expected results may provide evidence for defining cost-effective and globally scalable tools to estimate the risk of AD and address the needs of patients with memory complaints. In the era of DMTs, this will have crucial implications for the early identification of patients suitable for treatment in the initial stages of AD. TRIAL REGISTRATION NUMBER (TRN): NCT05569083.

Neural coding of autonomic functions in different states of consciousness.

Detecting signs of residual neural activity in patients with altered states of consciousness is a crucial issue for the customization of neurorehabilitation treatments and clinical decision-making. With this large observational prospective study, we propose an innovative approach to detect residual signs of consciousness via the assessment of the amount of autonomic information coded within the brain. The latter was estimated by computing the mutual information (MI) between preprocessed EEG and ECG signals, to be then compared across consciousness groups, together with the absolute power and an international qualitative labeling. One-hundred seventy-four patients (73 females, 42%) were included in the study (median age of 65 years [IQR = 20], MCS +: 29, MCS -: 23, UWS: 29). Electroencephalography (EEG) information content was found to be mostly related to the coding of electrocardiography (ECG) activity, i.e., with higher MI (p < 0.05), in Unresponsive Wakefulness Syndrome and Minimally Consciousness State minus (MCS -). EEG-ECG MI, besides clearly discriminating patients in an MCS - and +, significantly differed between lesioned areas (sides) in a subgroup of unilateral hemorrhagic patients. Crucially, such an accessible and non-invasive measure of residual consciousness signs was robust across electrodes and patient groups. Consequently, exiting from a strictly neuro-centric consciousness detection approach may be the key to provide complementary insights for the objective assessment of patients' consciousness levels and for the patient-specific planning of rehabilitative interventions.

Brain microstate spatio-temporal dynamics as a candidate endotype of consciousness.

Consciousness can be defined as a phenomenological experience continuously evolving. Current research showed how conscious mental activity can be subdivided into a series of atomic brain states converging to a discrete spatiotemporal pattern of global neuronal firing. Using the high temporal resolution of EEG recordings in patients with a severe Acquired Brain Injury (sABI) admitted to an Intensive Rehabilitation Unit (IRU), we detected a novel endotype of consciousness from the spatiotemporal brain dynamics identified via microstate analysis. Also, we investigated whether microstate features were associated with common neurophysiological alterations. Finally, the prognostic information comprised in such descriptors was analysed in a sub-cohort of patients with prolonged Disorder of Consciousness (pDoC). Occurrence of frontally-oriented microstates (C microstate), likelihood of maintaining such brain state or transitioning to the C topography and complexity were found to be indicators of consciousness presence and levels. Features of left-right asymmetric microstates and transitions toward them were found to be negatively correlated with antero-posterior brain reorganization and EEG symmetry. Substantial differences in microstates' sequence complexity and presence of C topography were found between groups of patients with alpha dominant background, cortical reactivity and antero-posterior gradient. Also, transitioning from left-right to antero-posterior microstates was found to be an independent predictor of consciousness recovery, stronger than consciousness levels at IRU's admission. In conclusions, global brain dynamics measured with scale-free estimators can be considered an indicator of consciousness presence and a candidate marker of short-term recovery in patients with a pDoC.

Quantitative EEG and prognosis for recovery in post-stroke patients: The effect of lesion laterality.

OBJECTIVE: There is emerging confidence that quantitative EEG (qEEG) has the potential to inform clinical decision-making and guide individualized rehabilitation after stroke, but consensus on the best EEG biomarkers is needed for translation to clinical practice. This study investigates the spatial qEEG spectral and symmetry distribution in patients with a left/right hemispheric stroke, to evaluate their side-specific prognostic power in post-acute rehabilitation outcome. METHODS: Resting-state 19-channel EEG recordings were collected with clinical information on admission to intensive inpatient rehabilitation (within 30 days post stroke), and six months post stroke. After preprocessing, spectral (Delta-to-Alpha Ratio, DAR) and symmetry (pairwise and hemispheric Brain Symmetry Index) features were extracted. Patients were divided into Affected Right and Left (AR/AL) groups, according to the location of their lesion. Within each group, DAR was compared between homologous electrode pairs and the pairwise difference between pairs was compared across pairs in the scalp. Then, the prognostic power of qEEG admission metrics was evaluated by performing correlations between admission metrics and discharge mBI values. RESULTS: Fifty-two patients with hemorrhagic or ischemic stroke (20 females, 38.5 %, median age 76 years [IQR = 22]) were included in the study. DAR was significantly higher in the affected hemisphere for both AR and AL groups, and, a higher frontal (to posterior) asymmetry was found independent of the side of the lesion. DAR was found to be a prognostic marker of 6-months modified Barthel Index (mBI) only for the AL group, while hemispheric asymmetry did not correlate with follow-up outcomes in either group. DISCUSSION: While the presence of EEG abnormalities in the affected hemisphere of a stroke is well recognized, we have shown that the extent of DAR abnormalities seen correlates with disability at 6 months post stroke, but only for left hemispheric lesions. Routine prognostic evaluation, in addition to motor and functional scales, can add information concerning neuro-prognostication and reveal neurophysiological abnormalities to be assessed during rehabilitation.

Personalized modeling of Alzheimer's disease progression estimates neurodegeneration severity from EEG recordings.

INTRODUCTION: Early identification of Alzheimer's disease (AD) is necessary for a timely onset of therapeutic care. However, cortical structural alterations associated with AD are difficult to discern. METHODS: We developed a cortical model of AD-related neurodegeneration accounting for slowing of local dynamics and global connectivity degradation. In a monocentric study we collected electroencephalography (EEG) recordings at rest from participants in healthy (HC, n = 17), subjective cognitive decline (SCD, n = 58), and mild cognitive impairment (MCI, n = 44) conditions. For each patient, we estimated neurodegeneration model parameters based on individual EEG recordings. RESULTS: Our model outperformed standard EEG analysis not only in discriminating between HC and MCI conditions (F1 score 0.95 vs 0.75) but also in identifying SCD patients with biological hallmarks of AD in the cerebrospinal fluid (recall 0.87 vs 0.50). DISCUSSION: Personalized models could (1) support classification of MCI, (2) assess the presence of AD pathology, and (3) estimate the risk of cognitive decline progression, based only on economical and non-invasive EEG recordings. Highlights: Personalized cortical model estimating structural alterations from EEG recordings.Discrimination of Mild Cognitive Impairment (MCI) and Healthy (HC) subjects (95%)Prediction of biological markers of Alzheimer's in Subjective Decline (SCD) Subjects (87%)Transition correctly predicted for 3/3 subjects that converted from SCD to MCI after 1y.

Low-density EEG-based Functional Connectivity Discriminates Minimally Conscious State plus from minus.

OBJECTIVE: Within the continuum of consciousness, patients in a Minimally Conscious State (MCS) may exhibit high-level behavioral responses (MCS+) or may not (MCS-). The evaluation of residual consciousness and related classification is crucial to propose tailored rehabilitation and pharmacological treatments, considering the inherent differences among groups in diagnosis and prognosis. Currently, differential diagnosis relies on behavioral assessments posing a relevant risk of misdiagnosis. In this context, EEG offers a non-invasive approach to model the brain as a complex network. The search for discriminating features could reveal whether behavioral responses in post-comatose patients have a defined physiological background. Additionally, it is essential to determine whether the standard behavioral assessment for quantifying responsiveness holds physiological significance. METHODS: In this prospective observational study, we investigated whether low-density EEG-based graph metrics could discriminate MCS+/- patients by enrolling 57 MCS patients (MCS-: 30; males: 28). At admission to intensive rehabilitation, 30 min resting-state closed-eyes EEG recordings were performed together with consciousness diagnosis following international guidelines. After EEG preprocessing, graphs' metrics were estimated using different connectivity measures, at multiple connection densities and frequency bands (α,θ,δ). Metrics were also provided to cross-validated Machine Learning (ML) models with outcome MCS+/-. RESULTS: A lower level of brain activity integration was found in the MCS- group in the α band. Instead, in the δ band MCS- group presented an higher level of clustering (weighted clustering coefficient) respect to MCS+. The best-performing solution in discriminating MCS+/- through the use of ML was an Elastic-Net regularized logistic regression with a cross-validation accuracy of 79% (sensitivity and specificity of 74% and 85% respectively). CONCLUSION: Despite tackling the MCS+/- differential diagnosis is highly challenging, a daily-routine low-density EEG might allow to differentiate across these differently responsive brain networks. SIGNIFICANCE: Graph-theoretical features are shown to discriminate between these two neurophysiologically similar conditions, and may thus support the clinical diagnosis.

Heart rate variability for the evaluation of patients with disorders of consciousness.

OBJECTIVE: Clinical responsiveness of patients with a Disorder of Consciousness (DoC) correlates to sympathetic/parasympathetic homeostatic balance. Heart Rate Variability (HRV) metrics result in non-invasive proxies of modulation capabilities of visceral states. In this work, our aim was to evaluate whether HRV measures could improve the differential diagnosis between Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS) with respect to multivariate models based on standard clinical electroencephalography (EEG) labeling only in a rehabilitation setting. METHODS: A prospective observational study was performed consecutively enrolling 82 DoC patients. Polygraphic recordings were performed. HRV-metrics and EEG descriptors derived from the American Clinical Neurophysiology Society's Standardized Critical Care terminology were included. Descriptors entered univariate and then multivariate logistic regressions with the target set to the UWS/MCS diagnosis. RESULTS: HRV measures resulted significantly different between UWS and MCS patients, with higher values being associated with better consciousness levels. Specifically, adding HRV-related metrics to ACNS EEG descriptors increased the Nagelkerke R2 from 0.350 (only EEG descriptors) to 0.565 (HRV-EEG combination) with the outcome set to the consciousness diagnosis. CONCLUSIONS: HRV changes across the lowest states of consciousness. Rapid changes in heart rate, occurring in better consciousness levels, confirm the mutual correlation between visceral state functioning patterns and consciousness alterations. SIGNIFICANCE: Quantitative analysis of heart rate in patients with a DoC paves the way for the implementation of low-cost pipelines supporting medical decisions within multimodal consciousness assessments.

EEG fractal dimensions predict high-level behavioral responses in minimally conscious patients.

Objective.Brain-injured patients may enter a state of minimal or inconsistent awareness termed minimally conscious state (MCS). Such patient may (MCS+) or may not (MCS-) exhibit high-level behavioral responses, and the two groups retain two inherently different rehabilitative paths and expected outcomes. We hypothesized that brain complexity may be treated as a proxy of high-level cognition and thus could be used as a neural correlate of consciousness.Approach.In this prospective observational study, 68 MCS patients (MCS-: 30; women: 31) were included (median [IQR] age 69 [20]; time post-onset 83 [28]). At admission to intensive rehabilitation, 30 min resting-state closed-eyes recordings were performed together with consciousness diagnosis following international guidelines. The width of the multifractal singularity spectrum (MSS) was computed for each channel time series and entered nested cross-validated interpretable machine learning models targeting the differential diagnosis of MCS±.Main results.Frontal MSS widths (p< 0.05), as well as the ones deriving from the left centro-temporal network (C3:p= 0.018, T3:p= 0.017; T5:p= 0.003) were found to be significantly higher in the MCS+ cohort. The best performing solution was found to be the K-nearest neighbor model with an aggregated test accuracy of 75.5% (median [IQR] AuROC for 100 executions 0.88 [0.02]). Coherently, the electrodes with highest Shapley values were found to be Fz and Cz, with four out the first five ranked features belonging to the fronto-central network.Significance.MCS+ is a frequent condition associated with a notably better prognosis than the MCS-. High fractality in the left centro-temporal network results coherent with neurological networks involved in the language function, proper of MCS+ patients. Using EEG-based interpretable algorithm to complement differential diagnosis of consciousness may improve rehabilitation pathways and communications with caregivers.

Degradation of EEG microstates patterns in subjective cognitive decline and mild cognitive impairment: Early biomarkers along the Alzheimer's Disease continuum?

Alzheimer's disease (AD) pathological changes may begin up to decades earlier than the appearance of the first symptoms of cognitive decline. Subjective cognitive decline (SCD) could be the first pre-clinical sign of possible AD, which might be followed by mild cognitive impairment (MCI), the initial stage of clinical cognitive decline. However, the neural correlates of these prodromic stages are not completely clear yet. Recent studies suggest that EEG analysis tools characterizing the cortical activity as a whole, such as microstates and cortical regions connectivity, might support a characterization of SCD and MCI conditions. Here we test this approach by performing a broad set of analyses to identify the prominent EEG markers differentiating SCD (n = 57), MCI (n = 46) and healthy control subjects (HC, n = 19). We found that the salient differences were in the temporal structure of the microstates patterns, with MCI being associated with less complex sequences due to the altered transition probability, frequency and duration of canonic microstate C. Spectral content of EEG, network connectivity, and spatial arrangement of microstates were instead largely similar in the three groups. Interestingly, comparing properties of EEG microstates in different cerebrospinal fluid (CSF) biomarkers profiles, we found that canonic microstate C displayed significant differences in topography in AD-like profile. These results show that the progression of dementia might be associated with a degradation of the cortical organization captured by microstates analysis, and that this leads to altered transitions between cortical states. Overall, our approach paves the way for the use of non-invasive EEG recordings in the identification of possible biomarkers of progression to AD from its prodromal states.