Spectral exponent assessment and neurofilament light chain: a comprehensive approach to describe recovery patterns in stroke.

Introduction: Understanding the residual recovery potential in stroke patients is crucial for tailoring effective neurorehabilitation programs. We propose using EEG and plasmatic Neurofilament light chain (NfL) levels as a model to depict longitudinal patterns of stroke recovery. Methods: We enrolled 13 patients (4 female, mean age 74.7 ± 8.8) who underwent stroke in the previous month and were hospitalized for 2-months rehabilitation. Patients underwent blood withdrawal, clinical evaluation and high-definition EEG at T1 (first week of rehabilitation) and at T2 (53 ± 10 days after). We assessed the levels of NfL and we analyzed the EEG signal extracting Spectral Exponent (SE) values. We compared our variables between the two timepoint and between cortical and non-cortical strokes. Results: We found a significant difference in the symmetry of SE values between cortical and non-cortical stroke at both T1 (p = 0.005) and T2 (p = 0.01). SE in the affected hemisphere showed significantly steeper values at T1 when compared with T2 (p = 0.001). EEG measures were consistently related to clinical scores, while NfL at T1 was related to the volume of ischemic lesions (r = 0.75; p = 0.003). Additionally, the combined use of NfL and SE indicated varying trends in longitudinal clinical recovery. Conclusion: We present proof of concept of a promising approach for the characterization of different recovery patterns in stroke patients.

Proof-of-concept evidence for high-density EEG investigation of sleep slow wave traveling in First-Episode Psychosis.

Schizophrenia is thought to reflect aberrant connectivity within cortico-cortical and reentrant thalamo-cortical loops, which physiologically integrate and coordinate the function of multiple cortical and subcortical structures. Despite extensive research, reliable biomarkers of such "dys-connectivity" remain to be identified at the onset of psychosis, and before exposure to antipsychotic drugs. Because slow waves travel across the brain during sleep, they represent an ideal paradigm to study pathological conditions affecting brain connectivity. Here, we provide proof-of-concept evidence for a novel approach to investigate slow wave traveling properties in First-Episode Psychosis (FEP) with high-density electroencephalography (EEG). Whole-night sleep recordings of 5 drug-naïve FEP and 5 age- and gender-matched healthy control subjects were obtained with a 256-channel EEG system. One patient was re-recorded after 6 months and 3 years of continuous clozapine treatment. Slow wave detection and traveling properties were obtained with an open-source toolbox. Slow wave density and slow wave traveled distance (measured as the line of longest displacement) were significantly lower in patients (p < 0.05). In the patient who was tested longitudinally during effective clozapine treatment, slow wave density normalized, while traveling distance only partially recovered. These preliminary findings suggest that slow wave traveling could be employed in larger samples to detect cortical "dys-connectivity" at psychosis onset.

Assessing mismatch negativity (MMN) and P3b within-individual sensitivity - A comparison between the local-global paradigm and two specialized oddball sequences.

Mismatch negativity (MMN) and P3b are well known for their clinical utility. There exists no gold standard, however, for acquiring them as EEG markers of consciousness in clinical settings. This may explain why the within-individual sensitivity of MMN/P3b paradigms is often quite poor and why seemingly identical EEG markers can behave differently across Disorders of consciousness (DoC) studies. Here, we compare two traditional paradigms for MMN or P3b assessment with the recently more popular local-global paradigm that promises to assess MMN and P3b orthogonally within one oddball sequence. All three paradigms were administered to healthy participants (N = 15) with concurrent EEG. A clear MMN and local effect were found for 15/15 participants. The P3b and global effect were found for 14/15 and 13/15 participants, respectively. There were no systematic differences between the global effect and P3b. Indeed, P3b amplitude was highly correlated across paradigms. The local effect differed clearly from the MMN, however. It occurred earlier than MMN and was followed by a much more prominent P3a. The peak latencies and amplitudes were also not correlated across paradigms. Caution should therefore be exercised when comparing the local effect and MMN across studies. We conclude that the within-individual MMN sensitivity is adequate for both the local-global and a dedicated MMN paradigm. The within-individual sensitivity of P3b was lower than expected for both the local-global and a dedicated P3b paradigm, which may explain the often-low sensitivity of P3b paradigms in patients with DoC.

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.

Thalamic feedback shapes brain responses evoked by cortical stimulation in mice and humans.

Cortical stimulation with single pulses is a common technique in clinical practice and research. However, we still do not understand the extent to which it engages subcortical circuits which contribute to the associated evoked potentials (EPs). Here we find that cortical stimulation generates remarkably similar EPs in humans and mice, with a late component similarly modulated by the subject's behavioral state. We optogenetically dissect the underlying circuit in mice, demonstrating that the late component of these EPs is caused by a thalamic hyperpolarization and rebound. The magnitude of this late component correlates with the bursting frequency and synchronicity of thalamic neurons, modulated by the subject's behavioral state. A simulation of the thalamo-cortical circuit highlights that both intrinsic thalamic currents as well as cortical and thalamic GABAergic neurons contribute to this response profile. We conclude that the cortical stimulation engages cortico-thalamo-cortical circuits highly preserved across different species and stimulation modalities.

The maturation of aperiodic EEG activity across development reveals a progressive differentiation of wakefulness from sleep.

During development, the brain undergoes radical structural and functional changes following a posterior-to-anterior gradient, associated with profound changes of cortical electrical activity during both wakefulness and sleep. However, a systematic assessment of the developmental effects on aperiodic EEG activity maturation across vigilance states is lacking, particularly regarding its topographical aspects. Here, in a population of 160 healthy infants, children and teenagers (from 2 to 17 years, 10 subjects for each year), we investigated the development of aperiodic EEG activity in wakefulness and sleep. Specifically, we parameterized the shape of the aperiodic background of the EEG Power Spectral Density (PSD) by means of the spectral exponent and offset; the exponent reflects the rate of exponential decay of power over increasing frequencies and the offset reflects an estimate of the y-intercept of the PSD. We found that sleep and development caused the EEG-PSD to rotate over opposite directions: during wakefulness the PSD showed a flatter decay and reduced offset over development, while during sleep it showed a steeper decay and a higher offset as sleep becomes deeper. During deep sleep (N2, N3) only the spectral offset decreased over age, indexing a broad-band voltage reduction. As a result, the difference between values in deep sleep and those in both light sleep (N1) and wakefulness increased with age, suggesting a progressive differentiation of wakefulness from sleep EEG activity, most prominent over the frontal regions, the latest to complete maturation. Notably, the broad-band spectral exponent values during deep sleep stages were entirely separated from wakefulness values, consistently across developmental ages and in line with previous findings in adults. Concerning topographical development, the location showing the steepest PSD decay and largest offset shifted from posterior to anterior regions with age. This shift, particularly evident during deep sleep, paralleled the migration of sleep slow wave activity and was consistent with neuroanatomical and cognitive development. Overall, aperiodic EEG activity distinguishes wakefulness from sleep regardless of age; while, during development, it reveals a postero-anterior topographical maturation and a progressive differentiation of wakefulness from sleep. Our study could help to interpret changes due to pathological conditions and may elucidate the neurophysiological processes underlying the development of wakefulness and sleep.

An in-vivo validation of ESI methods with focal sources.

Electrophysiological source imaging (ESI) aims at reconstructing the precise origin of brain activity from measurements of the electric field on the scalp. Across laboratories/research centers/hospitals, ESI is performed with different methods, partly due to the ill-posedness of the underlying mathematical problem. However, it is difficult to find systematic comparisons involving a wide variety of methods. Further, existing comparisons rarely take into account the variability of the results with respect to the input parameters. Finally, comparisons are typically performed using either synthetic data, or in-vivo data where the ground-truth is only roughly known. We use an in-vivo high-density EEG dataset recorded during intracranial single pulse electrical stimulation, in which the true sources are substantially dipolar and their locations are precisely known. We compare ten different ESI methods, using their implementation in the MNE-Python package: MNE, dSPM, LORETA, sLORETA, eLORETA, LCMV beamformers, irMxNE, Gamma Map, SESAME and dipole fitting. We perform comparisons under multiple choices of input parameters, to assess the accuracy of the best reconstruction, as well as the impact of such parameters on the localization performance. Best reconstructions often fall within 1 cm from the true source, with most accurate methods hitting an average localization error of 1.2 cm and outperforming least accurate ones erring by 2.5 cm. As expected, dipolar and sparsity-promoting methods tend to outperform distributed methods. For several distributed methods, the best regularization parameter turned out to be the one in principle associated with low SNR, despite the high SNR of the available dataset. Depth weighting played no role for two out of the six methods implementing it. Sensitivity to input parameters varied widely between methods. While one would expect high variability being associated with low localization error at the best solution, this is not always the case, with some methods producing highly variable results and high localization error, and other methods producing stable results with low localization error. In particular, recent dipolar and sparsity-promoting methods provide significantly better results than older distributed methods. As we repeated the tests with "conventional" (32 channels) and dense (64, 128, 256 channels) EEG recordings, we observed little impact of the number of channels on localization accuracy; however, for distributed methods denser montages provide smaller spatial dispersion. Overall findings confirm that EEG is a reliable technique for localization of point sources and therefore reinforce the importance that ESI may have in the clinical context, especially when applied to identify the surgical target in potential candidates for epilepsy surgery.

TMS-EEG and resting-state EEG applied to altered states of consciousness: oscillations, complexity, and phenomenology.

Exploring the neurobiology of the profound changes in consciousness induced by classical psychedelic drugs may require novel neuroimaging methods. Serotonergic psychedelic drugs such as psilocybin produce states of increased sensory-emotional awareness and arousal, accompanied by increased spontaneous electroencephalographic (EEG) signal diversity. By directly stimulating cortical tissue, the altered dynamics and propagation of the evoked EEG activity can reveal drug-induced changes in the overall brain state. We combine Transcranial Magnetic Stimulation (TMS) and EEG to reveal that psilocybin produces a state of increased chaotic brain activity which is not a result of altered complexity in the underlying causal interactions between brain regions. We also map the regional effects of psilocybin on TMS-evoked activity and identify changes in frontal brain structures that may be associated with the phenomenology of psychedelic experiences.

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.

Measures of differentiation and integration: One step closer to consciousness.

Interpreting empirical measures of integration and differentiation as indices of cortical performance and memory consolidation during wakefulness rather than consciousness per se is inconsistent with the literature. Recent studies show that these theory-inspired measures can dissociate from such processes and reliably index the brain's capacity for experience. We consider this as a positive trend in consciousness research.

Reduced readiness potential and post-movement beta synchronization reflect self-disorders in early course schizophrenia.

Disturbances of conscious awareness, or self-disorders, are a defining feature of schizophrenia. These include symptoms such as delusions of control, i.e. the belief that one's actions are controlled by an external agent. Models of self-disorders point at altered neural mechanisms of source monitoring, i.e. the ability of the brain to discriminate self-generated stimuli from those driven by the environment. However, evidence supporting this putative relationship is currently lacking. We performed electroencephalography (EEG) during self-paced, brisk right fist closures in ten (M = 9; F = 1) patients with Early-Course Schizophrenia (ECSCZ) and age and gender-matched healthy volunteers. We measured the Readiness Potential (RP), i.e. an EEG feature preceding self-generated movements, and movement-related EEG spectral changes. Self-disorders in ECSCZ were assessed with the Examination of Anomalous Self-Experience (EASE). Patients showed a markedly reduced RP and altered post-movement Event-Related Synchronization (ERS) in the beta frequency band (14-24 Hz) compared to healthy controls. Importantly, smaller RP and weaker ERS were associated with higher EASE scores in ECSCZ. Our data suggest that disturbances of neural correlates preceding and following self-initiated movements may reflect the severity of self-disorders in patients suffering from ECSCZ. These findings point towards deficits in basic mechanisms of sensorimotor integration as a substrate for self-disorders.

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

The distinctive sleep pattern of the human calcarine cortex: a stereo-electroencephalographic study.

STUDY OBJECTIVES: The aim of this study was to describe the spontaneous electroencephalographic (EEG) features of sleep in the human calcarine cortex, comparing them with the well-established pattern of the parietal cortex. METHODS: We analyzed presurgical intracerebral EEG activity in calcarine and parietal cortices during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in seven patients with drug-resistant focal epilepsy. The time course of the EEG spectral power and NREM vs REM differences was assessed. Sleep spindles were automatically detected. To assess homeostatic dynamics, we considered the first vs second half of the night ratio in the delta frequency range (0.5-4 Hz) and the rise rate of delta activity during the first sleep cycle. RESULTS: While the parietal area showed the classically described NREM and REM sleep hallmarks, the calcarine cortex exhibited a distinctive pattern characterized by: (1) the absence of sleep spindles; (2) a large similarity between EEG power spectra of NREM and REM; and (3) reduced signs of homeostatic dynamics, with a decreased delta ratio between the first and the second half of the night, a reduced rise rate of delta activity during the first NREM sleep cycle, and lack of correlation between these measures. CONCLUSIONS: Besides describing for the first time the peculiar sleep EEG pattern in the human calcarine cortex, our findings provide evidence that different cortical areas may exhibit specific sleep EEG pattern, supporting the view of sleep as a local process and promoting the idea that the functional role of sleep EEG features should be considered at a regional level.

Information Optimized Multilayer Network Representation of High Density Electroencephalogram Recordings.

High-density electroencephalography (hd-EEG) provides an accessible indirect method to record spatio-temporal brain activity with potential for disease diagnosis and monitoring. Due to their highly multidimensional nature, extracting useful information from hd-EEG recordings is a complex task. Network representations have been shown to provide an intuitive picture of the spatial connectivity underlying an electroencephalogram recording, although some information is lost in the projection. Here, we propose a method to construct multilayer network representations of hd-EEG recordings that maximize their information content and test it on sleep data recorded in individuals with mental health issues. We perform a series of statistical measurements on the multilayer networks obtained from patients and control subjects and detect significant differences between the groups in clustering coefficient, betwenness centrality, average shortest path length and parieto occipital edge presence. In particular, patients with a mood disorder display a increased edge presence in the parieto-occipital region with respect to healthy control subjects, indicating a highly correlated electrical activity in that region of the brain. We also show that multilayer networks at constant edge density perform better, since most network properties are correlated with the edge density itself which can act as a confounding factor. Our results show that it is possible to stratify patients through statistical measurements on a multilayer network representation of hd-EEG recordings. The analysis reveals that individuals with mental health issues display strongly correlated signals in the parieto-occipital region. Our methodology could be useful as a visualization and analysis tool for hd-EEG recordings in a variety of pathological conditions.

Thalamic and neocortical differences in the relationship between the time course of delta and sigma power during NREM sleep in humans.

Sleep spindles and slow waves are the hallmarks of non-rapid eye movement (NREM) sleep and are produced by the dynamic interplay between thalamic and cortical regions. Several studies in both human and animal models have focused their attention on the relationship between electroencephalographic (EEG) spindles and slow waves during NREM, using the power in the sigma and delta bands as a surrogate for the production of spindles and slow waves. A typical report is an overall inverse relationship between the time course of sigma and delta power as measured by a single correlation coefficient both within and across NREM episodes. Here we analysed stereotactically implanted intracerebral electrode (Stereo-EEG [SEEG]) recordings during NREM simultaneously acquired from thalamic and from several neocortical sites in six neurosurgical patients. We investigated the relationship between the time course of delta and sigma power and found that, although at the cortical level it shows the expected inverse relationship, these two frequency bands follow a parallel time course at the thalamic level. Both these observations were consistent across patients and across different cortical as well as thalamic regions. These different temporal dynamics at the neocortical and thalamic level are discussed, considering classical as well as more recent interpretations of the neurophysiological determinants of sleep spindles and slow waves. These findings may also help understanding the regulatory mechanisms of these fundamental sleep EEG graphoelements across different brain compartments.

Consciousness and complexity: a consilience of evidence.

Over the last years, a surge of empirical studies converged on complexity-related measures as reliable markers of consciousness across many different conditions, such as sleep, anesthesia, hallucinatory states, coma, and related disorders. Most of these measures were independently proposed by researchers endorsing disparate frameworks and employing different methods and techniques. Since this body of evidence has not been systematically reviewed and coherently organized so far, this positive trend has remained somewhat below the radar. The aim of this paper is to make this consilience of evidence in the science of consciousness explicit. We start with a systematic assessment of the growing literature on complexity-related measures and identify their common denominator, tracing it back to core theoretical principles and predictions put forward more than 20 years ago. In doing this, we highlight a consistent trajectory spanning two decades of consciousness research and provide a provisional taxonomy of the present literature. Finally, we consider all of the above as a positive ground to approach new questions and devise future experiments that may help consolidate and further develop a promising field where empirical research on consciousness appears to have, so far, naturally converged.

Local sleep-like cortical reactivity in the awake brain after focal injury.

The functional consequences of focal brain injury are thought to be contingent on neuronal alterations extending beyond the area of structural damage. This phenomenon, also known as diaschisis, has clinical and metabolic correlates but lacks a clear electrophysiological counterpart, except for the long-standing evidence of a relative EEG slowing over the injured hemisphere. Here, we aim at testing whether this EEG slowing is linked to the pathological intrusion of sleep-like cortical dynamics within an awake brain. We used a combination of transcranial magnetic stimulation and electroencephalography (TMS/EEG) to study cortical reactivity in a cohort of 30 conscious awake patients with chronic focal and multifocal brain injuries of ischaemic, haemorrhagic and traumatic aetiology. We found that different patterns of cortical reactivity typically associated with different brain states (coma, sleep, wakefulness) can coexist within the same brain. Specifically, we detected the occurrence of prominent sleep-like TMS-evoked slow waves and off-periods-reflecting transient suppressions of neuronal activity-in the area surrounding focal cortical injuries. These perilesional sleep-like responses were associated with a local disruption of signal complexity whereas complex responses typical of the awake brain were present when stimulating the contralesional hemisphere. These results shed light on the electrophysiological properties of the tissue surrounding focal brain injuries in humans. Perilesional sleep-like off-periods can disrupt network activity but are potentially reversible, thus representing a principled read-out for the neurophysiological assessment of stroke patients, as well as an interesting target for rehabilitation.