Central autonomic network and early prognosis in patients with disorders of consciousness.

The central autonomic network (CAN) plays a crucial role in modulating the autonomic nervous system. Heart rate variability (HRV) is a valuable marker for assessing CAN function in disorders of consciousness (DOC) patients. We used HRV analysis for early prognosis in 58 DOC patients enrolled within ten days of hospitalization. They underwent a five-minute electrocardiogram during baseline and acoustic/visual stimulation. The coma recovery scale-revised (CRS-R) was used to define the patient's consciousness level and categorize the good/bad outcome at three months. The high-frequency Power Spectrum Density and the standard deviation of normal-to-normal peaks in baseline, the sample entropy during the stimulation, and the time from injury features were used in the support vector machine analysis (SVM) for outcome prediction. The SVM predicted the patients' outcome with an accuracy of 96% in the training test and 100% in the validation test, underscoring its potential to provide crucial clinical information about prognosis.

Assessing Consciousness through Neurofeedback and Neuromodulation: Possibilities and Challenges.

Neurofeedback is a non-invasive therapeutic approach that has gained traction in recent years, showing promising results for various neurological and psychiatric conditions. It involves real-time monitoring of brain activity, allowing individuals to gain control over their own brainwaves and improve cognitive performance or alleviate symptoms. The use of electroencephalography (EEG), such as brain-computer interface (BCI), transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS), has been instrumental in developing neurofeedback techniques. However, the application of these tools in patients with disorders of consciousness (DoC) presents unique challenges. In this narrative review, we explore the use of neurofeedback in treating patients with DoC. More specifically, we discuss the advantages and challenges of using tools such as EEG neurofeedback, tDCS, TMS, and BCI for these conditions. Ultimately, we hope to provide the neuroscientific community with a comprehensive overview of neurofeedback and emphasize its potential therapeutic applications in severe cases of impaired consciousness levels.

I Feel! Therefore, I Am from Pain to Consciousness in DOC Patients.

Pain assessment and management in patients with disorders of consciousness (DOC) is a challenging and important aspect of care, with implications for detecting consciousness and promoting recovery. This narrative review explores the role of pain in consciousness, the challenges of pain assessment, pharmacological treatment in DOC, and the implications of pain assessment when detecting changes in consciousness. The review discusses the Nociception Coma Scale and its revised version, which are behavioral scales used to assess pain in DOC patients, and the challenges and controversies surrounding the appropriate pharmacological treatment of pain in these patients. Moreover, we highlight recent evidence suggesting that an accurate pain assessment may predict changes in the level of consciousness in unresponsive wakefulness syndrome/vegetative state patients, underscoring the importance of ongoing pain management in these patients.

Behavioral scales variability in patients with prolonged disorders of consciousness.

BACKGROUND: The principal conditions differentiating disorders of consciousness (DOC) patients are the unresponsive wakefulness syndrome/vegetative state (UWS/VS) and the minimally conscious state (MCS). Many individuals who suffer from sudden-onset severe brain injury move through stages of UWS/VS and MCS before regaining full awareness. In some patients, the DOC condition is protracted for years (PDOC). In this study, we observed PDOC patients for 6 months to assess possible changes in their level of consciousness. METHODS: We enrolled 40 PDOC patients, 23 UWS/VS and 17 MCS hosted in a dedicated unit for long-term brain injury care. The time from injury was 472 ± 533 days for UWS/VS and 1090 ± 1079 days for MCS. The Wessex Head Injury Matrix (WHIM), Coma Recovery Scale-R (CRS-R), and Nociception Coma Scale were administered monthly for 6 months. RESULTS: During the period of assessment, the percentage of UWS/VS shifted from 58 to 45%, while for the MCS, from 42 to 55%. A positive correlation was found for the UWS/VS patients between the months of observation with the CRS-R total score and WHIM total numbers of behaviors (TNB). In the UWS/VS group, the CRS-R auditive and visual subscales correlated positively with the observation time. During the whole period of observation, 8 patients had constant CRS-R total scores while the WHIM TNB changed in 7 of them. CONCLUSION: Our findings demonstrated that the monthly assessment of PDOC by means of the CRS-R and WHIM was able to detect also subtle changes in consciousness level.

Heart Rate Complexity and Autonomic Modulation Are Associated with Psychological Response Inhibition in Healthy Subjects.

BACKGROUND: the ability to suppress/regulate impulsive reactions has been identified as common factor underlying the performance in all executive function tasks. We analyzed the HRV signals (power of high (HF) and low (LF) frequency, Sample Entropy (SampEn), and Complexity Index (CI)) during the execution of cognitive tests to assess flexibility, inhibition abilities, and rule learning. METHODS: we enrolled thirty-six healthy subjects, recording five minutes of resting state and two tasks of increasing complexity based on 220 visual stimuli with 12 × 12 cm red and white squares on a black background. RESULTS: at baseline, CI was negatively correlated with age, and LF was negatively correlated with SampEn. In Task 1, the CI and LF/HF were negatively correlated with errors. In Task 2, the reaction time positively correlated with the CI and the LF/HF ratio errors. Using a binary logistic regression model, age, CI, and LF/HF ratio classified performance groups with a sensitivity and specificity of 73 and 71%, respectively. CONCLUSIONS: this study performed an important initial exploration in defining the complex relationship between CI, sympathovagal balance, and age in regulating impulsive reactions during cognitive tests. Our approach could be applied in assessing cognitive decline, providing additional information on the brain-heart interaction.

Wessex Head Injury Matrix in Patients with Prolonged Disorders of Consciousness: A Reliability Study.

Introduction: The Wessex Head Injury Matrix (WHIM) was developed to assess patients with disorders of consciousness (DOC) and was tested in terms of inter-rater reliability (IRR) and test-retest reliability (TRR) in the year 2000. The American Congress of Rehabilitation and Medicine reported that IRR and TRR were unproven. We aim to assess the reliability of the WHIM in prolonged DOC patients (PDOC). Methods: A total of 51 PDOC patients (32 unresponsive wakefulness syndrome (UWS/VS) and 19 minimally conscious state (MCS)) who were hosted in a dedicated unit for long-term brain injury care were enrolled. The time from injury ranged from 182 to 3325 days. Two raters administered the Coma Recovery Scale-Revised (CRS-R) and the WHIM to test the IRR and TRR. The TRR was administered two weeks after the first assessment. Results: For the CRS-R, the agreement in IRR and TRR was perfect between the two raters. The agreement for the WHIM ranged from substantial to almost perfect for IRR and from fair to substantial for the TRR. Conclusions: The WHIM showed a strong IRR when administered by expert raters and strongly correlated with the CRS-R. This study provides further evidence of the psychometric qualities of the WHIM and the importance of its use in PDOC patients.

Inhibitory Control and Brain-Heart Interaction: An HRV-EEG Study.

BACKGROUND: Motor inhibition is a complex cognitive function regulated by specific brain regions and influenced by the activity of the Central Autonomic Network. We investigate the two-way Brain-Heart interaction during a Go/NoGo task. Spectral EEG ϑ, α powerbands, and HRV parameters (Complexity Index (CI), Low Frequency (LF) and High Frequency (HF) powers) were recorded. METHODS: Fourteen healthy volunteers were enrolled. We used a modified version of the classical Go/NoGo task, based on Rule Shift Cards, characterized by a baseline and two different tasks of different complexity. The participants were divided into subjects with Good (GP) and Poor (PP) performances. RESULTS: In the baseline, CI was negatively correlated with α/ϑ. In task 1, the CI was negatively correlated with the errors and α/ϑ, while the errors were positively correlated with α/ϑ. In task 2, CI was negatively correlated with the Reaction Time and positively with α, and the errors were negatively correlated with the Reaction Time and positively correlated with α/ϑ. The GP group showed, at baseline, a negative correlation between CI and α/ϑ. CONCLUSIONS: We provide a new combined Brain-Heart model underlying inhibitory control abilities. The results are consistent with the complementary role of α and ϑ oscillations in cognitive control.

Heart rate complexity: An early prognostic marker of patient outcome after cardiac arrest.

OBJECTIVE: Early prognostication in comatose patients after cardiac arrest (CA) is difficult but essential to inform relatives and optimize treatment. Here we investigate the predictive value of heart-rate variability captured by multiscale entropy (MSE) for long-term outcomes in comatose patients during the first 24 hours after CA. METHODS: In this retrospective analysis of prospective multi-centric cohort, we analyzed MSE of the heart rate in 79 comatose patients after CA while undergoing targeted temperature management and sedation during the first day of coma. From the MSE, two complexity indices were derived by summing values over short and long time scales (CIs and CIl). We splitted the data in training and test datasets for analysing the predictive value for patient outcomes (defined as best cerebral performance category within 3 months) of CIs and CIl. RESULTS: Across the whole dataset, CIl provided the best sensitivity, specificity, and accuracy (88%, 75%, and 82%, respectively). Positive and negative predictive power were 81% and 84%. CONCLUSIONS: Characterizing the complexity of the ECG in patients after CA provides an accurate prediction of both favorable and unfavorable outcomes. SIGNIFICANCE: The analysis of heartrate variability by means of MSE provides accurate outcome prediction on the first day of coma.

The Timecourse of Electrophysiological Brain-Heart Interaction in DoC Patients.

Disorders of Consciousness (DOC) are a spectrum of pathologies affecting one's ability to interact with the external world. Two possible conditions of patients with DOC are Unresponsive Wakefulness Syndrome/Vegetative State (UWS/VS) and Minimally Conscious State (MCS). Analysis of spontaneous EEG activity and the Heart Rate Variability (HRV) are effective techniques in exploring and evaluating patients with DOC. This study aims to observe fluctuations in EEG and HRV parameters in the morning/afternoon resting-state recording. The study enrolled 13 voluntary Healthy Control (HC) subjects and 12 DOC patients (7 MCS, 5 UWS/VS). EEG and EKG were recorded. PSDalpha, PSDtheta powerband, alpha-blocking, alpha/theta of the EEG, Complexity Index (CI) and SDNN of EKG were analyzed. Higher values of PSDalpha, alpha-blocking, alpha/theta and CI values and lower values of PSD theta characterized HC individuals in the morning with respect to DOC patients. In the afternoon, we detected a significant difference between groups in the CI, PSDalpha, PSDtheta, alpha/theta and SDNN, with lower PSDtheta value for HC. CRS-R scores showed a strong correlation with recorded parameters mainly during evaluations in the morning. Our finding put in evidence the importance of the assessment, as the stimulation of DOC patients in research for behavioural response, in the morning.

Nociceptive Response Is a Possible Marker of Evolution in the Level of Consciousness in Unresponsive Wakefulness Syndrome Patients.

The Nociception Coma Scale (NCS) and its revised version (NCS-R) were used to evaluate behavioral responses to pain in non-communicative patients. We hypothesized that if patients demonstrate changes to their NCS(-R) scores over time, their evolving behavioral abilities could indicate a forthcoming diagnostic improvement with the Coma Recovery Scale-Revised (CRS-R). Forty-three Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients were enrolled in the study. The patients were assessed weekly using the CRS-R and NCS(-R) for four consecutive weeks. The first assessment was within 10 days after hospitalization. The assessments were performed between 09:30 and 11:30 AM in a room with constant levels of humidity, light and temperature, as well as an absence of transient noise. Noxious stimuli were administered using a Newton-meter, with pressure applied to the fingernail bed for a maximum of 5 s unless interrupted by a behavioral response from subjects. Seventeen patients demonstrated improvements in their level of consciousness, 13 of whom showed significant behavioral changes through the NCS(-R) before being diagnosed with a Minimally Conscious State (MCS) according to the CRS-R. The behavioral changes observed using the NCS(-R) corresponded to a high probability of observing an improvement from VS/UWS to MCS. To characterize the increased likelihood of this transition, our results present threshold scores of ≥5 for the NCS (accuracy 86%, sensitivity 87%, and specificity 86%) and ≥3 for the NCS-R (accuracy 77%, sensitivity 89%, and specificity 73%). In conclusion, a careful evaluation of responses to nociceptive stimuli in DOC patients could constitute an effective procedure in assessing their evolving conscious state.

Diagnostic Developments in Differentiating Unresponsive Wakefulness Syndrome and the Minimally Conscious State.

When treating patients with a disorder of consciousness (DOC), it is essential to obtain an accurate diagnosis as soon as possible to generate individualized treatment programs. However, accurately diagnosing patients with DOCs is challenging and prone to errors when differentiating patients in a Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) from those in a Minimally Conscious State (MCS). Upwards of ~40% of patients with a DOC can be misdiagnosed when specifically designed behavioral scales are not employed or improperly administered. To improve diagnostic accuracy for these patients, several important neuroimaging and electrophysiological technologies have been proposed. These include Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI), Electroencephalography (EEG), and Transcranial Magnetic Stimulation (TMS). Here, we review the different ways in which these techniques can improve diagnostic differentiation between VS/UWS and MCS patients. We do so by referring to studies that were conducted within the last 10 years, which were extracted from the PubMed database. In total, 55 studies met our criteria (clinical diagnoses of VS/UWS from MCS as made by PET, fMRI, EEG and TMS- EEG tools) and were included in this review. By summarizing the promising results achieved in understanding and diagnosing these conditions, we aim to emphasize the need for more such tools to be incorporated in standard clinical practice, as well as the importance of data sharing to incentivize the community to meet these goals.

The Emergence of Integrated Information, Complexity, and 'Consciousness' at Criticality.

Integrated Information Theory (IIT) posits that integrated information ( Φ ) represents the quantity of a conscious experience. Here, the generalized Ising model was used to calculate Φ as a function of temperature in toy models of fully connected neural networks. A Monte-Carlo simulation was run on 159 normalized, random, positively weighted networks analogous to small five-node excitatory neural network motifs. Integrated information generated by this sample of small Ising models was measured across model parameter spaces. It was observed that integrated information, as an order parameter, underwent a phase transition at the critical point in the model. This critical point was demarcated by the peak of the generalized susceptibility (or variance in configuration due to temperature) of integrated information. At this critical point, integrated information was maximally receptive and responsive to perturbations of its own states. The results of this study provide evidence that Φ can capture integrated information in an empirical dataset, and display critical behavior acting as an order parameter from the generalized Ising model.

The Trace Conditional Learning of the Noxious Stimulus in UWS Patients and Its Prognostic Value in a GSR and HRV Entropy Study.

The assessment of the consciousness level of Unresponsive Wakefulness Syndrome (UWS) patients often depends on a subjective interpretation of the observed spontaneous and volitional behavior. To date, the misdiagnosis level is around 30%. The aim of this study was to observe the behavior of UWS patients, during the administration of noxious stimulation by a Trace Conditioning protocol, assessed by the Galvanic Skin Response (GSR) and Heart Rate Variability (HRV) entropy. We recruited 13 Healthy Control (HC) and 30 UWS patients at 31 ± 9 days from the acute event evaluated by Coma Recovery Scale-Revised (CRS-R) and Nociception Coma Scale (NCS). Two different stimuli [musical stimulus (MUS) and nociceptive stimulus (NOC)], preceded, respectively by two different tones, were administered following the sequences (A) MUS1 - NOC1 - MUS2 - MUS3 - NOC2 - MUS4 - NOC3 - NOC*, and (B) MUS1*, NOC1*, NOC2*, MUS2*, NOC3*, MUS3*, NOC4*, MUS4*. All the (*) indicate the only tones administration. CRS-R and NCS assessments were repeated for three consecutive weeks. MUS4, NOC3, and NOC* were compared for GSR wave peak magnitude, time to reach the peak, and time of wave's decay by Wilcoxon's test to assess the Conditioned Response (CR). The Sample Entropy (SampEn) was recorded in baseline and both sequences. Machine Learning approach was used to identify a rule to discriminate the CR. The GSR magnitude of CR was higher comparing music stimulus (p < 0.0001) and CR extinction (p < 0.002) in nine patients and in HC. Patients with CR showed a higher SampEn in sequence A compared to patients without CR. Within the third and fourth weeks from protocol administration, eight of the nine patients (88.9%) evolved into MCS. The Machine-learning showed a high performance to differentiate presence/absence of CR (≥95%). The possibility to observe the CR to the noxious stimulus, by means of the GSR and SampEn, can represent a potential method to reduce the misdiagnosis in UWS patients.

Measures of CNS-Autonomic Interaction and Responsiveness in Disorder of Consciousness.

Neuroimaging studies have demonstrated functional interactions between autonomic (ANS) and brain (CNS) structures involved in higher brain functions, including attention and conscious processes. These interactions have been described by the Central Autonomic Network (CAN), a concept model based on the brain-heart two-way integrated interaction. Heart rate variability (HRV) measures proved reliable as non-invasive descriptors of the ANS-CNS function setup and are thought to reflect higher brain functions. Autonomic function, ANS-mediated responsiveness and the ANS-CNS interaction qualify as possible independent indicators for clinical functional assessment and prognosis in Disorders of Consciousness (DoC). HRV has proved helpful to investigate residual responsiveness in DoC and predict clinical recovery. Variability due to internal (e.g., homeostatic and circadian processes) and environmental factors remains a key independent variable and systematic research with this regard is warranted. The interest in bidirectional ANS-CNS interactions in a variety of physiopathological conditions is growing, however, these interactions have not been extensively investigated in DoC. In this brief review we illustrate the potentiality of brain-heart investigation by means of HRV analysis in assessing patients with DoC. The authors' opinion is that this easy, inexpensive and non-invasive approach may provide useful information in the clinical assessment of this challenging patient population.

Circadian Rhythms and Measures of CNS/Autonomic Interaction.

The physiological role and relevance of the mechanisms sustaining circadian rhythms have been acknowledged. Abnormalities of the circadian and/or sleep-wakefulness cycles can result in major metabolic disorders or behavioral/professional inadequacies and stand as independent risk factors for metabolic, psychiatric, and cerebrovascular disorders and early markers of disease. Neuroimaging and clinical evidence have documented functional interactions between autonomic (ANS) and CNS structures that are described by a concept model (Central Autonomic Network) based on the brain-heart two-way interplay. The circadian rhythms of autonomic function, ANS-mediated processes, and ANS/CNS interaction appear to be sources of variability adding to a variety of environmental factors, and may become crucial when considering the ANS major role in internal environment constancy and adaptation that are fundamental to homeostasis. The CNS/ANS interaction has not yet obtained full attention and systematic investigation remains overdue.

The Reliability of the Progression of Autonomies Scale Applied on Acquired Brain Injured Patients.

The Progression of Autonomies Scale (PAS) is a behavioral scale useful to assess the autonomy levels in acquired brain-injured patients. It provides a broad profile, assessing different domains of human activities ranging from personal, domestic, and extradomestic autonomies. This cross-sectional study is aimed at evaluating the reliability of this scale on a large cohort of acquired brain injury (ABI) patients. Fifty-one ABI patients (49% traumatic, 33.3% hemorrhagic, 17.7% other etiologies), hospitalized in the S. Anna Institute of Crotone, Italy (mean age male 46.08 ± 14.53 and mean age female patients 43.2 ± 11.3) were recruited. We found a high level of reliability of the scale, with a coefficient at the inter-rater agreement between substantial (0.61 ≤ k ≤ 0.8) and almost perfect (0.81 ≤ k ≤ 1), and almost perfect at the test-retest (intra-rater). We confirm that the PAS is a well-structured tool for the assessment of the autonomy levels in brain-injured patients. These findings encourage the application of this scale in the clinical practice of rehabilitation unit to design a tailored rehabilitation treatment on real goals and to monitor the generalization of the recovered abilities to the daily routine activities.

Heart Rate Variability as an Indicator of Nociceptive Pain in Disorders of Consciousness?

CONTEXT: Heart rate variability is thought to reflect the affective and physiological aspects of pain and is emerging as a possible descriptor of the functional brain organization contributing to homeostasis. OBJECTIVES: To investigate whether the short-term Complexity Index (CIs), a measure of heart rate variability complexity is useful to discriminate responses to potentially noxious and nonnoxious stimulation in patients with different levels of consciousness. METHODS: Twenty-two patients (11 minimally conscious state [MCS], 11 vegetative state/unresponsive wakefulness syndrome [VS/UWS]) and 14 healthy controls (HC) were enrolled. We recorded the electrocardiographic response and calculated the CIs before (baseline), during, and after nonnoxious and noxious stimulation. Mann-Whitney and Wilcoxon's tests were used to investigate differences in CIs according to the level of consciousness (i.e., HC vs. patients and VS/UWS vs. MCS) and the three conditions (i.e., baseline, nonnoxious, noxious). The correlation between the three conditions and the Coma Recovery Scale-Revised was investigated by Spearman's correlations. RESULTS: We observed higher CIs values in HC as compared with patients during the baseline (P < 0.034) and after the noxious stimulation (P < 0.0001). We also found higher values in MCS versus VS/UWS patients after the noxious condition (P < 0.001) and lower values in the noxious versus nonnoxious condition solely for the VS/UWS group (P < 0.007). A correlation was found between CIs in noxious condition and Coma Recovery Scale-Revised scores. CONCLUSION: Our results suggest a less complex autonomic response to noxious stimuli in VS/UWS patients. Such method may help to better understand sympathovagal response to potentially painful stimulation in brain-injured patients.

Do Sensory Stimulation Programs Have an Impact on Consciousness Recovery?

Objectives: Considering sensory stimulation programs (SSP) as a treatment for disorders of consciousness is still debated today. Previous studies investigating its efficacy were affected by various biases among which small sample size and spontaneous recovery. In this study, treatment-related changes were assessed using time-series design in patients with disorders of consciousness (i.e., vegetative state-VS and minimally conscious state-MCS). Methods: A withdrawal design (ABAB) was used. During B phases, patients underwent a SSP (3 days a week, including auditory, visual, tactile, olfactory, and gustatory stimulation). The program was not applied during A phases. To assess behavioral changes, the Coma Recovery Scale-Revised (CRS-R) was administered by an independent rater on a weekly basis, across all phases. Each phase lasted 4 weeks. In a subset of patients, resting state functional magnetic resonance imaging (fMRI) data were collected at the end of each phase. Results: Twenty nine patients (48 ± 19 years old; 15 traumatic; 21 > a year post-injury; 11 VS and 18 MCS) were included in our study. Higher CRS-R total scores (medium effect size) as well as higher arousal and oromotor subscores were observed in the B phases (treatment) as compared to A phases (no treatment), in the MCS group but not in the VS group. In the three patients who underwent fMRI analyses, a modulation of metabolic activity related to treatment was observed in middle frontal gyrus, superior temporal gyrus as well as ventro-anterior thalamic nucleus. Conclusion: Our results suggest that SSP may not be sufficient to restore consciousness. SSP might nevertheless lead to improved behavioral responsiveness in MCS patients. Our results show higher CRS-R total scores when treatment is applied, and more exactly, increased arousal and oromotor functions.

A Heartbeat Away From Consciousness: Heart Rate Variability Entropy Can Discriminate Disorders of Consciousness and Is Correlated With Resting-State fMRI Brain Connectivity of the Central Autonomic Network.

Background: Disorders of consciousness are challenging to diagnose, with inconsistent behavioral responses, motor and cognitive disabilities, leading to approximately 40% misdiagnoses. Heart rate variability (HRV) reflects the complexity of the heart-brain two-way dynamic interactions. HRV entropy analysis quantifies the unpredictability and complexity of the heart rate beats intervals. We here investigate the complexity index (CI), a score of HRV complexity by aggregating the non-linear multi-scale entropies over a range of time scales, and its discriminative power in chronic patients with unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), and its relation to brain functional connectivity. Methods: We investigated the CI in short (CIs) and long (CIl) time scales in 14 UWS and 16 MCS sedated. CI for MCS and UWS groups were compared using a Mann-Whitney exact test. Spearman's correlation tests were conducted between the Coma Recovery Scale-revised (CRS-R) and both CI. Discriminative power of both CI was assessed with One-R machine learning model. Correlation between CI and brain connectivity (detected with functional magnetic resonance imagery using seed-based and hypothesis-free intrinsic connectivity) was investigated using a linear regression in a subgroup of 10 UWS and 11 MCS patients with sufficient image quality. Results: Higher CIs and CIl values were observed in MCS compared to UWS. Positive correlations were found between CRS-R and both CI. The One-R classifier selected CIl as the best discriminator between UWS and MCS with 90% accuracy, 7% false positive and 13% false negative rates after a 10-fold cross-validation test. Positive correlations were observed between both CI and the recovery of functional connectivity of brain areas belonging to the central autonomic networks (CAN). Conclusion: CI of MCS compared to UWS patients has high discriminative power and low false negative rate at one third of the estimated human assessors' misdiagnosis, providing an easy, inexpensive and non-invasive diagnostic tool. CI reflects functional connectivity changes in the CAN, suggesting that CI can provide an indirect way to screen and monitor connectivity changes in this neural system. Future studies should assess the extent of CI's predictive power in a larger cohort of patients and prognostic power in acute patients.