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Loss of consciousness is a hallmark of many epileptic seizures and carries risks of serious injury and sudden death. While cortical sleep-like activities accompany loss of consciousness during focal impaired awareness seizures, the mechanisms of loss of consciousness during focal to bilateral tonic-clonic seizures remain unclear. Quantifying differences in markers of cortical activation and ictal recruitment between focal impaired awareness and focal to bilateral tonic-clonic seizures may also help us to understand their different consequences for clinical outcomes and to optimize neuromodulation therapies. We quantified clinical signs of loss of consciousness and intracranial EEG activity during 129 focal impaired awareness and 50 focal to bilateral tonic-clonic from 41 patients. We characterized intracranial EEG changes both in the seizure onset zone and in areas remote from the seizure onset zone with a total of 3386 electrodes distributed across brain areas. First, we compared the dynamics of intracranial EEG sleep-like activities: slow-wave activity (1–4 Hz) and beta/delta ratio (a validated marker of cortical activation) during focal impaired awareness versus focal to bilateral tonic-clonic. Second, we quantified differences between focal to bilateral tonic-clonic and focal impaired awareness for a marker validated to detect ictal cross-frequency coupling: phase-locked high gamma (high-gamma phased-locked to low frequencies) and a marker of ictal recruitment: the epileptogenicity index. Third, we assessed changes in intracranial EEG activity preceding and accompanying behavioural generalization onset and their correlation with electromyogram channels. In addition, we analysed human cortical multi-unit activity recorded with Utah arrays during three focal to bilateral tonic-clonic seizures. Compared to focal impaired awareness, focal to bilateral tonic-clonic seizures were characterized by deeper loss of consciousness, even before generalization occurred. Unlike during focal impaired awareness, early loss of consciousness before generalization was accompanied by paradoxical decreases in slow-wave activity and by increases in high-gamma activity in parieto-occipital and temporal cortex. After generalization, when all patients displayed loss of consciousness, stronger increases in slow-wave activity were observed in parieto-occipital cortex, while more widespread increases in cortical activation (beta/delta ratio), ictal cross-frequency coupling (phase-locked high gamma) and ictal recruitment (epileptogenicity index). Behavioural generalization coincided with a whole-brain increase in high-gamma activity, which was especially synchronous in deep sources and could not be explained by EMG. Similarly, multi-unit activity analysis of focal to bilateral tonic-clonic revealed sustained increases in cortical firing rates during and after generalization onset in areas remote from the seizure onset zone. Overall, these results indicate that unlike during focal impaired awareness, the neural signatures of loss of consciousness during focal to bilateral tonic-clonic consist of paradoxical increases in cortical activation and neuronal firing found most consistently in posterior brain regions. These findings suggest differences in the mechanisms of ictal loss of consciousness between focal impaired awareness and focal to bilateral tonic-clonic and may account for the more negative prognostic consequences of focal to bilateral tonic-clonic.

Diagnostic and prognostic assessment of patients with disorders of consciousness (DoC) presents ethical and clinical implications as they may affect the course of medical treatment and the decision to withdraw life-sustaining therapy. There has been increasing research in this field to lower misdiagnosis rates by developing standardized and consensual tools to detect consciousness. In this article, we summarize recent evidence regarding behavioral signs that are not yet included in the current clinical guidelines but could detect consciousness. The new potential behavioral signs of consciousness described here are as follows: resistance to eye opening, spontaneous eye blink rate, auditory localization, habituation of auditory startle reflex, olfactory sniffing, efficacy of swallowing/oral feeding, leg crossing, facial expressions to noxious stimulation, and subtle motor behaviors. All of these signs show promising results in discriminating patients' level of consciousness. Multimodal studies with large sample sizes in different centers are needed to further evaluate whether these behaviors reliably indicate the presence of consciousness. Future translation of these research findings into clinical practice has potential to improve the accuracy of diagnosis and prognostication for patients with DoC.

This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.

The relationship between temporal lobe epilepsy and psychopathology has had a long and contentious history with diverse views regarding the presence, nature and severity of emotional–behavioural problems in this patient population. To address these controversies, we take a new person-centred approach through the application of unsupervised machine learning techniques to identify underlying latent groups or behavioural phenotypes. Addressed are the distinct psychopathological profiles, their linked frequency, patterns and severity and the disruptions in morphological and network properties that underlie the identified latent groups. A total of 114 patients and 83 controls from the Epilepsy Connectome Project were administered the Achenbach System of Empirically Based Assessment inventory from which six Diagnostic and Statistical Manual of Mental Disorders-oriented scales were analysed by unsupervised machine learning analytics to identify latent patient groups. Identified clusters were contrasted to controls as well as to each other in order to characterize their association with sociodemographic, clinical epilepsy and morphological and functional imaging network features. The concurrent validity of the behavioural phenotypes was examined through other measures of behaviour and quality of life. Patients overall exhibited significantly higher (abnormal) scores compared with controls. However, cluster analysis identified three latent groups: (i) unaffected, with no scale elevations compared with controls (Cluster 1, 37%); (ii) mild symptomatology characterized by significant elevations across several Diagnostic and Statistical Manual of Mental Disorders-oriented scales compared with controls (Cluster 2, 42%); and (iii) severe symptomatology with significant elevations across all scales compared with controls and the other temporal lobe epilepsy behaviour phenotype groups (Cluster 3, 21%). Concurrent validity of the behavioural phenotype grouping was demonstrated through identical stepwise links to abnormalities on independent measures including the National Institutes of Health Toolbox Emotion Battery and quality of life metrics. There were significant associations between cluster membership and sociodemographic (handedness and education), cognition (processing speed), clinical epilepsy (presence and lifetime number of tonic–clonic seizures) and neuroimaging characteristics (cortical volume and thickness and global graph theory metrics of morphology and resting-state functional MRI). Increasingly dispersed volumetric abnormalities and widespread disruptions in underlying network properties were associated with the most abnormal behavioural phenotype. Psychopathology in these patients is characterized by a series of discrete latent groups that harbour accompanying sociodemographic, clinical and neuroimaging correlates. The underlying neurobiological patterns suggest that the degree of psychopathology is linked to increasingly dispersed abnormal brain networks. Similar to cognition, machine learning approaches support a novel developing taxonomy of the comorbidities of epilepsy.

The brain mechanisms of memory consolidation remain elusive. Here, we examine blood-oxygen-level-dependent (BOLD) correlates of image recognition through the scope of multiple influential systems consolidation theories. We utilize the longitudinal Natural Scenes Dataset, a 7-Tesla functional magnetic resonance imaging human study in which ∼135,000 trials of image recognition were conducted over the span of a year among eight subjects. We find that early- and late-stage image recognition associates with both medial temporal lobe (MTL) and visual cortex when evaluating regional activations and a multivariate classifier. Supporting multiple-trace theory (MTT), parts of the MTL activation time course show remarkable fit to a 20-y-old MTT time-dynamical model predicting early trace intensity increases and slight subsequent interference ( R 2 > 0.90). These findings contrast a simplistic, yet common, view that memory traces are transferred from MTL to cortex. Next, we test the hypothesis that the MTL trace signature of memory consolidation should also reflect synaptic “desaturation,” as evidenced by an increased signal-to-noise ratio. We find that the magnitude of relative BOLD enhancement among surviving memories is positively linked to the rate of removal (i.e., forgetting) of competing traces. Moreover, an image-feature and time interaction of MTL and visual cortex functional connectivity suggests that consolidation mechanisms improve the specificity of a distributed trace. These neurobiological effects do not replicate on a shorter timescale (within a session), implicating a prolonged, offline process. While recognition can potentially involve cognitive processes outside of memory retrieval (e.g., re-encoding), our work largely favors MTT and desaturation as perhaps complementary consolidative memory mechanisms.

The target article misrepresents the foundations of integrated information theory (IIT) and ignores many essential publications. It, thus, falls to this lead commentary to outline the axioms and postulates of IIT and correct major misconceptions. The commentary also explains why IIT starts from phenomenology and why it predicts that only select physical substrates can support consciousness. Finally, it highlights that IIT's account of experience – a cause–effect structure quantified by integrated information – has nothing to do with “information transfer.”

Strong conceptual and theoretical connections have been made between meditation practice, mindfulness and lucid dreaming. However, only a handful of empirical studies have evaluated the relationship between lucid dreaming and meditation, and conclusions remain tempered by methodological limitations. Here we evaluate the relationship between meditation, mindfulness and lucid dream frequency using several complementary methods. First, using a cross-sectional design, we evaluate differences in lucid dream frequency between long-term meditators and meditation naïve individuals. Second, we evaluate the relationship between lucid dream frequency and specific facets of trait mindfulness in both meditators and non-meditators. Third, using a blinded randomized-controlled design, we evaluate the impact of an 8-week mindfulness course on lucid dreaming frequency. Our results show that lucid dreaming is more frequent in long-term meditators compared to meditation naïve individuals. Additionally, lucid dream frequency in meditation-naïve individuals was associated with a capacity to verbalize experience, while lucid dream frequency in long-term meditators was associated with observational and decentering facets of trait mindfulness. However, an 8-week mindfulness course did not increase the frequency of lucid dreams. Together these results support a continuity between increased awareness of waking and sleeping states, provide a novel form of evidence linking meditation training to meta-awareness, and support an association between meditation practice and lucid dreaming, but leave open the specific nature of this connection.

We report a case of primary diffuse leptomeningeal gliomatosis (PDLG) in a 76-year-old male presenting with confusion, dysarthria, diplopia, lumbal pain and headaches of recent onset. Neurological examination revealed nuchal rigidity and bilateral sixth cranial nerve palsy. The cerebrospinal fluid showed a marked hyperproteinorachia (4711 mg/L) and mild cytorachia (5-10 leucocytes/mm3) with a few atypical lymphoid cells. On admission, brain CT scan and MRI demonstrated diffuse and nodular leptomeningeal contrast enhancement predominant at the skull base and several osteolytic lesions in the right parietal bone. Extensive serological studies for infectious, autoimmune or neoplastic diseases were negative. The work-up diagnosis was neurosarcoidosis or multiple meningeal and osseous metastases of an unknown primary cancer. Surgical biopsy of the right parietal bone lesion showed only fibrous tissue with no evidence of tumour or inflammation. The patient was treated with high dose corticosteroids but its neurological status progressively worsened and he died of aspiration pneumonia 35 days after admission. Post-mortem examination revealed a PDLG, a rare fatal tumour with about 60 cases reported. PDGL is characterized by the diffusion of neoplastic glial cells throughout the leptomeninges without evidence of a primary intra-parenchymal lesion. Recognition of this rare brain tumour is important as recent reports suggest that radiotherapy and chemotherapy can improve patient survival.

Traumatic and non-traumatic brain injured disorders of consciousness patients are still challenging for diagnosis, prognosis, ethical and socio-economic reasons. Currently, there remains a high rate of misdiagnosis of the vegetative state (Schnakers, et al. 2009). Recent advances in MRI techniques (diffusion tensor, magnetic resonance spectroscopy and functional imaging) provide data that could improve the diagnostic and prognostic evaluation and management of these patients.

Assessing the level of consciousness of noncommunicative brain-damaged patients is difficult, as one has to make inferences based on the patients' behavior. However, behavioral responses of brain-damaged patients are usually limited not only by their cognitive dysfunctions, but also by their frequent motor impairment. For these reasons, it is essential to resort to para-clinical markers of the level of consciousness. In recent years, a number of studies compared brain activity in comatose and vegetative state patients to that in healthy volunteers, and in other conditions of reduced consciousness such as sleep, anesthesia, or epileptic seizures. Despite the increasing amount of experimental results, no consensus on the brain mechanisms generating consciousness has yet been reached. Here, we discuss the need to combine a theoretical approach with current experimental procedures to obtain a coherent, parsimonious explanation for the loss of consciousness in several different conditions, such as coma, vegetative state, sleep, anesthesia, and epileptic seizures. In our view, without a theoretical account of how conscious experience is generated by the brain, it will remain difficult to understand the mechanisms underlying the generation of consciousness, and to predict reliably its presence or absence in noncommunicative brain-damaged patients. In this context, we review current theoretical approaches to consciousness, and how well they fit with current evidence on the neural correlates of experience. Specifically, we emphasize the principled approach provided by the Integrated Information Theory of Consciousness (IITC). We describe the different conditions where the theory predicts markedly reduced states of consciousness, and discuss several technical and conceptual issues limiting its applicability to measuring the level of consciousness of individual patients. Nevertheless, we argue that some of the predictions of the theory are potentially testable using available imaging techniques.

How do we evaluate a brain's capacity to sustain conscious experience if the subject does not manifest purposeful behaviour and does not respond to questions and commands? What should we measure in this case? An emerging idea in theoretical neuroscience is that what really matters for consciousness in the brain is not activity levels, access to sensory inputs or neural synchronization per se, but rather the ability of different areas of the thalamocortical system to interact causally with each other to form an integrated whole. In particular, the information integration theory of consciousness (IITC) argues that consciousness is integrated information and that the brain should be able to generate consciousness to the extent that it has a large repertoire of available states (information), yet it cannot be decomposed into a collection of causally independent subsystems (integration). To evaluate the ability to integrate information among distributed cortical regions, it may not be sufficient to observe the brain in action. Instead, it is useful to employ a perturbational approach and examine to what extent different regions of the thalamocortical system can interact causally (integration) and produce specific responses (information). Thanks to a recently developed technique, transcranial magnetic stimulation and high-density electroencephalography (TMS/hd-EEG), one can record the immediate reaction of the entire thalamocortical system to controlled perturbations of different cortical areas. In this chapter, using sleep as a model of unconsciousness, we show that TMS/hd-EEG can detect clear-cut changes in the ability of the thalamocortical system to integrate information when the level of consciousness fluctuates across the sleep-wake cycle. Based on these results, we discuss the potential applications of this novel technique to evaluate objectively the brain's capacity for consciousness at the bedside of brain-injured patients.

Disorders of consciousness (DOC) raise profound scientific, clinical, ethical, and philosophical issues. Growing knowledge on fundamental principles of brain organization in healthy individuals offers new opportunities for a better understanding of residual brain function in DOCs. We here discuss new perspectives derived from a recently proposed scheme of brain organization underlying consciousness in healthy individuals. In this scheme, thalamo-cortical networks can be divided into two, often antagonistic, global systems: (i) a system of externally oriented, sensory-motor networks (the "extrinsic" system); and (ii) a system of inward-oriented networks (the "intrinsic" or default system). According to this framework, four distinct mental states would be possible that could be relevant for understanding DOCs. In normal healthy volunteers and locked-in syndrome patients, a state of high functionality of both the extrinsic and intrinsic or default systems is expected--associated with full awareness of environment and self. In this case, mental imagery tasks combined with fMRI can be used to detect covert awareness in patients that are unable to communicate. According to the framework, two complementary states of system imbalance are also possible, in which one system is in a hyperfunctional state, while the other is hypoactive. Extrinsic system hyperfunction is expected to lead to a state of total sensory-motor "absorption" or "lost self." In contrast, intrinsic or default system hyperfunction is expected to lead to a state of complete detachment from the external world. A state where both extrinsic and intrinsic systems are hypofunctional is predicted to lead to markedly impaired consciousness as seen in DOCs. Finally, we review the potential use of ultra-slow fluctuations in BOLD signal as a tool for assessing the functional integrity of extrinsic and intrinsic systems during "resting state" fMRI acquisitions. In particular, we discuss the potential provided by assessment of these slow spontaneous BOLD fluctuations as a novel tool in assessing the cognitive state and chances of recovery from brain pathologies underlying DOCs.

The lockedin syndrome (LIS) originates from a ventro-pontine lesion resulting in a complete quadraplegia and anarthria. Classically, communication remains possible by means of spared vertical eye movements and/or blinking. To allow assessing cognitive functions in LIS patients, we propose here a neuropsychological testing based on eye-coded communication. Ten chronic LIS survivors were assessed 1 to 6 years after their brain insult.One patient was evaluated subacutely (at 2 months) and retested at 6 and 16 months.Neuropsychological testing encompassed short- and long-term memory, attention, executive functioning, phonological and semantic processing and verbal intelligence. None of the patients showed alterations in verbal intelligence. Impairments in one or several tests were found in five patients. In three of these patients, neuropsychological deficits could be related to additional cortical or thalamic structural brain lesions. In the other 2 patients, weakness or signs of fatigue only were observed in one or two cognitive tasks. Repeated measures in a subacute patient with pure brainstem lesion indicate the recovery of good levels of cognition 6 months after injury. Results indicate that LIS patients can recover intact cognitive levels in cases of pure brainstem lesions, and that additional brain injuries are most likely responsible for associated cognitive deficits in the LIS. Furthermore, a systematic neuropsychological assessment in LIS patients would allow detecting their cognitive deficits,which will contribute to improve their quality of life and of communication with family and medical caretakers.

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates for glucose are massively reduced in this condition. However, the recovery of consciousness from vegetative state is not always associated with substantial changes in global metabolism. This finding led us to hypothesize that some vegetative patients are unconscious not just because of a global loss of neuronal function, but rather due to an altered activity in some critical brain regions and to the abolished functional connections between them. We used voxel-based Statistical Parametric Mapping (SPM) approaches to characterize the functional neuroanatomy of the vegetative state. The most dysfunctional brain regions were bilateral frontal and parieto-temporal associative cortices. Despite the metabolic impairment, external stimulation still induced a significant neuronal activation (i.e. change in blood flow) in vegetative patients as shown by both auditory click stimuli and noxious somatosensory stimuli. However, this activation was limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. Finally, we demonstrated that vegetative patients have impaired functional connections between distant cortical areas and between the thalami and the cortex and, more importantly, that recovery of consciousness is paralleled by a restoration of this cortico-thalamo-cortical interaction., Journal Article, Research Support, Non-U.S. Gov't, Review, info:eu-repo/semantics/published

Prin "Connage" (Italian Government) European Union (EU) James S. McDonnell Foundation Scholar Award Belgian National Fund for Scientific Research Templeton World Charity Foundation McDonnell Foundation Distinguished Chair in Consciousness Science at the University of Wisconsin ObjectiveValidating 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 consciousnessthe 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). MethodsThe 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]). ResultsWe 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. InterpretationGiven 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 Univ Milan, Dept Biomed & Clin Sci L Sacco, Via GB Grassi 74, I-20157 Milan, Italy Fdn Europea Ric Biomed, Milan, Italy Univ Milano Bicocca, Sch Med & Surg, Dept Hlth Sci, Monza, Italy Univ Fed Sao Paulo, Inst Sci & Technol, Sao Jose Dos Campos, Brazil Fdn Don Gnocchi Onlus, Ist Ricovero & Cura Carattere Sci, Milan, Italy Univ Wisconsin, Dept Psychiat, Madison, WI 53706 USA Univ Wisconsin, Dept Neurol, Madison, WI 53706 USA Univ Liege, Coma Sci Grp, GIGA, Liege, Belgium Univ Liege, Dept Neurol, Liege, Belgium Univ Hosp Liege, Liege, Belgium Grande Osped Metropolitano Niguarda Ca Granda, Neurocrit Care Unit, Azienda Sociosanit Terr, Dept Neurosci, Milan, Italy Institute of Science and Technology, Universidade Federal de São Paulo (UNIFESP), São José dos Campos, Brazil EU: 600806 EU: 686764 EU: 720270 Web of Science

The relationship between the Bispectral Index (BIS), an EEG-based monitor of anesthesia, and brain activity is still unclear. This study aimed at investigating the relationship between changes in BIS values during natural sleep and regional cerebral blood flow (rCBF) variations, as measured by Positron Emission Tomography (PET). Data were obtained from six young, healthy, right-handed, male volunteers (20-30 years old) using the H2(15)O infusion method. PET scans were performed both during waking and various stages of sleep. BIS values were monitored continuously and recorded during each PET scan. Positive correlations were detected between BIS and rCBF values in dorsolateral prefontal, parietal, anterior and posterior cingulate, precuneal, mesiofrontal, mesiotemporal and insular cortices. These areas belong to a frontoparietal network known to be related to awareness of self conscious sensory perception, attention and memory. BIS values also positively correlated with activity in brainstem and thalami, both structures known to be involved in arousal and wakefulness. These results show that BIS changes associated with physiological sleep depth co-vary with the activity of specific cortical and subcortical areas. The latter are known to modulate arousal, which in turn allows sustained thalamo-cortical enhancement of activity in a specific frontoparietal network known to be related to the content of consciousness. Thus, although mainly derived from frontal EEG, BIS could represent a wider index of cerebral activity.

Currently, there remains a high rate of misdiagnosis of the vegetative state. This should incite clinicians to use the most sensitive "coma scales" to detect signs of consciousness in these patients. The gold standard remains the Glasgow Coma Scale (GCS, Teasdale and Jennet, 1974), with the Glasgow Liège Scale (GLS, Born, 1988) adding standardized assessment of brainstem reflexes. New sensible behavioral assessment tools for use in the acute neurocritical care setting include the Full Outline of UnResponsiveness (FOUR, Wijdicks et al., 2005). The Coma Recovery Scale-Revised (CRS-R, Giacino and Kalmar, 2004) specifically tests the diagnostic criteria differentiating vegetative from minimally conscious patients. Detecting signs of consciousness also depends on the employed methodology. We showed that for the assesment of the presence of visual pursuit, using a moving mirror is better suited than using a moving object or person. The clinical diagnosis can be confirmed by cerebral positron emission tomography studies objectively quantifying residual metabolic activity in vegetative and minimally conscious patients. Ongoing studies evaluate the prognostic value of functional magnetic resonance imaging studies in these challenging patient populations.

Most patients who remain comatose for a few hours after a period of global cerebral ischemia have a poor prognosis. Early identification of these patients is desirable to reduce uncertainty about treatment and non-treatment decisions, and to improve relationships with the family. The absence of pupillary light response and corneal reflexes, absent or stereotyped extension motor response to noxious stimulation (3 days after insult); myoclonus status epilepticus; absence of cortical N20 response on somatosensory evoked potential studies; generalised suppression or burst-suppression EEG and serum neuron-specific enolase above 33 microg/L (sampled 1-3 days after insult) have been shown to predict poor outcome. We here propose an algorithm to help intensive care physicians' clinical decision making in post-anoxic coma.