Family caregivers' sense-making of the results of functional neurodiagnostics for patients with Prolonged Disorders of Consciousness.

Functional neuroimaging and electrophysiological assessments can identify evidence of residual consciousness and cognition in patients with prolonged disorders of consciousness (PDOC) who are otherwise behaviourally unresponsive. These functional neurodiagnostics are increasingly available in clinical settings and are recommended by international clinical guidelines to reduce diagnostic and prognostic uncertainty, and thereby assist family caregivers in their best-interests decision-making. Nevertheless, little is known about how family caregivers make sense of the results of these state-of-the-art functional neurodiagnostics. By applying Interpretative Phenomenological Analysis (IPA) to interviews with family caregivers of patients with diagnoses of PDOC who had received a functional neurodiagnostic assessment, we identify three primary themes of sense-making: The special significance of "brain scans"; A dynamic sense-making process; Holding on to hope and holding on to the person. These themes highlight the challenges of helping family caregivers to balance the relative importance of functional neurodiagnostic results with other clinical assessments and identify an ability of family caregivers to hold a contradiction in which they hope for recovery but simultaneously express a rational understanding of evidence to the contrary. We offer several recommendations for the ways in which family caregivers can be better supported to make sense of the results of functional neurodiagnostics.

Attention modulates neural measures associated with beat perception.

A growing body of evidence suggests that steady-state evoked potentials may be a useful measure of beat perception, particularly when obtaining traditional, explicit measures of beat perception is difficult, such as with infants or non-human animals. Although attending to a stimulus is not necessary for most traditional applications of steady-state evoked potentials, it is unknown how attention affects steady-state evoked potentials that arise in response to beat perception. Additionally, most applications of steady-state evoked potentials to measure beat perception have used repeating rhythms or real music. Therefore, it is unclear how the steady-state response relates to the robust beat perception that occurs with non-repeating rhythms. Here, we used electroencephalography to record participants' brain activity as they listened to non-repeating musical rhythms while either attending to the rhythms or while distracted by a concurrent visual task. Non-repeating auditory rhythms elicited steady-state evoked potentials at perceived beat frequencies (perception was validated in a separate sensorimotor synchronization task) that were larger when participants attended to the rhythms compared with when they were distracted by the visual task. Therefore, although steady-state evoked potentials appear to index beat perception to non-repeating musical rhythms, this technique may be limited to when participants are known to be attending to the stimulus.

The impact of prolonged disorders of consciousness on family caregivers' quality of life - A scoping review.

Providing long-term care for a family member diagnosed with a Prolonged Disorder of Consciousness (PDoC) can have a significant impact on the lives of family caregivers. This scoping review aimed to explore the current literature investigating the impact of caring for a person in a PDoC on family caregivers' Quality of Life (QOL), as categorized using the WHOQOL-BREF model. We observed that articles employing quantitative methodologies mostly reported QOL outcomes relating to negative feelings, thinking, learning, memory and concentration, and personal relationships. Articles employing qualitative methodologies mostly reported QOL outcomes relating to negative feelings, personal relationships, positive feelings, and health and social care accessibility and quality. A descriptive content analysis of the QOL outcomes highlighted the limitations of the current literature base in representing the complexities of the experiences of family members providing care for a person in a PDoC. To provide valuable and personalized support to caregivers, without pathologizing or medicalizing their distress, it is vital to characterize more accurately the contextual subtleties of each person's situation.

Conscious processing of narrative stimuli synchronizes heart rate between individuals.

Heart rate has natural fluctuations that are typically ascribed to autonomic function. Recent evidence suggests that conscious processing can affect the timing of the heartbeat. We hypothesized that heart rate is modulated by conscious processing and therefore dependent on attentional focus. To test this, we leverage the observation that neural processes synchronize between subjects by presenting an identical narrative stimulus. As predicted, we find significant inter-subject correlation of heart rate (ISC-HR) when subjects are presented with an auditory or audiovisual narrative. Consistent with our hypothesis, we find that ISC-HR is reduced when subjects are distracted from the narrative, and higher ISC-HR predicts better recall of the narrative. Finally, patients with disorders of consciousness have lower ISC-HR, as compared to healthy individuals. We conclude that heart rate fluctuations are partially driven by conscious processing, depend on attentional state, and may represent a simple metric to assess conscious state in unresponsive patients.

The Influence of Auditory Attention on Rhythmic Speech Tracking: Implications for Studies of Unresponsive Patients.

Language comprehension relies on integrating words into progressively more complex structures, like phrases and sentences. This hierarchical structure-building is reflected in rhythmic neural activity across multiple timescales in E/MEG in healthy, awake participants. However, recent studies have shown evidence for this "cortical tracking" of higher-level linguistic structures also in a proportion of unresponsive patients. What does this tell us about these patients' residual levels of cognition and consciousness? Must the listener direct their attention toward higher level speech structures to exhibit cortical tracking, and would selective attention across levels of the hierarchy influence the expression of these rhythms? We investigated these questions in an EEG study of 72 healthy human volunteers listening to streams of monosyllabic isochronous English words that were either unrelated (scrambled condition) or composed of four-word-sequences building meaningful sentences (sentential condition). Importantly, there were no physical cues between four-word-sentences. Rather, boundaries were marked by syntactic structure and thematic role assignment. Participants were divided into three attention groups: from passive listening (passive group) to attending to individual words (word group) or sentences (sentence group). The passive and word groups were initially naïve to the sentential stimulus structure, while the sentence group was not. We found significant tracking at word- and sentence rate across all three groups, with sentence tracking linked to left middle temporal gyrus and right superior temporal gyrus. Goal-directed attention to words did not enhance word-rate-tracking, suggesting that word tracking here reflects largely automatic mechanisms, as was shown for tracking at the syllable-rate before. Importantly, goal-directed attention to sentences relative to words significantly increased sentence-rate-tracking over left inferior frontal gyrus. This attentional modulation of rhythmic EEG activity at the sentential rate highlights the role of attention in integrating individual words into complex linguistic structures. Nevertheless, given the presence of high-level cortical tracking under conditions of lower attentional effort, our findings underline the suitability of the paradigm in its clinical application in patients after brain injury. The neural dissociation between passive tracking of sentences and directed attention to sentences provides a potential means to further characterise the cognitive state of each unresponsive patient.

#EEGManyLabs: Investigating the replicability of influential EEG experiments.

There is growing awareness across the neuroscience community that the replicability of findings about the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardised analysis pipelines. Inspired by recent efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations.

The prognostic value of resting-state EEG in acute post-traumatic unresponsive states.

Accurate early prognostication is vital for appropriate long-term care decisions after traumatic brain injury. While measures of resting-state EEG oscillations and their network properties, derived from graph theory, have been shown to provide clinically useful information regarding diagnosis and recovery in patients with chronic disorders of consciousness, little is known about the value of these network measures when calculated from a standard clinical low-density EEG in the acute phase post-injury. To investigate this link, we first validated a set of measures of oscillatory network features between high-density and low-density resting-state EEG in healthy individuals, thus ensuring accurate estimation of underlying cortical function in clinical recordings from patients. Next, we investigated the relationship between these features and the clinical picture and outcome of a group of 18 patients in acute post-traumatic unresponsive states who were not following commands 2 days+ after sedation hold. While the complexity of the alpha network, as indexed by the standard deviation of the participation coefficients, was significantly related to the patients' clinical picture at the time of EEG, no network features were significantly related to outcome at 3 or 6 months post-injury. Rather, mean relative alpha power across all electrodes improved the accuracy of outcome prediction at 3 months relative to clinical features alone. These results highlight the link between the alpha rhythm and clinical signs of consciousness and suggest the potential for simple measures of resting-state EEG band power to provide a coarse snapshot of brain health for stratification of patients for rehabilitation, therapy and assessments of both covert and overt cognition.

Covert Speech Comprehension Predicts Recovery From Acute Unresponsive States.

OBJECTIVE: Patients with traumatic brain injury who fail to obey commands after sedation-washout pose one of the most significant challenges for neurological prognostication. Reducing prognostic uncertainty will lead to more appropriate care decisions and ensure provision of limited rehabilitation resources to those most likely to benefit. Bedside markers of covert residual cognition, including speech comprehension, may reduce this uncertainty. METHODS: We recruited 28 patients with acute traumatic brain injury who were 2 to 7 days sedation-free and failed to obey commands. Patients heard streams of isochronous monosyllabic words that built meaningful phrases and sentences while their brain activity via electroencephalography (EEG) was recorded. In healthy individuals, EEG activity only synchronizes with the rhythm of phrases and sentences when listeners consciously comprehend the speech. This approach therefore provides a measure of residual speech comprehension in unresponsive patients. RESULTS: Seventeen and 16 patients were available for assessment with the Glasgow Outcome Scale Extended (GOSE) at 3 months and 6 months, respectively. Outcome significantly correlated with the strength of patients' acute cortical tracking of phrases and sentences (r > 0.6, p < 0.007), quantified by inter-trial phase coherence. Linear regressions revealed that the strength of this comprehension response (beta = 0.603, p = 0.006) significantly improved the accuracy of prognoses relative to clinical characteristics alone (eg, Glasgow Coma Scale [GCS], computed tomography [CT] grade). INTERPRETATION: A simple, passive, auditory EEG protocol improves prognostic accuracy in a critical period of clinical decision making. Unlike other approaches to probing covert cognition for prognostication, this approach is entirely passive and therefore less susceptible to cognitive deficits, increasing the number of patients who may benefit. ANN NEUROL 2021;89:646-656.

Resting-State Electroencephalography for Prognosis in Disorders of Consciousness Following Traumatic Brain Injury.

Although the majority of patients recover consciousness after a traumatic brain injury (TBI), a minority develop a prolonged disorder of consciousness, which may never fully resolve. For these patients, accurate prognostication is essential to treatment decisions and long-term care planning. In this review, we evaluate the use of resting-state electroencephalography (EEG) as a prognostic measure in disorders of consciousness following TBI. We highlight that routine clinical EEG recordings have prognostic utility in the short to medium term. In particular, measures of alpha power and variability are indicative of relatively better functional outcomes within the first year post-TBI. This is hypothesized to reflect intact thalamocortical loops, and thus the potential for recovery of consciousness even in the apparent absence of current consciousness. However, there is a lack of research into the use of resting-state EEG for predicting longer-term recovery following TBI. We conclude that, given the potential for patients to demonstrate improvements in consciousness and functional capacity even years after TBI, a research focus on EEG-augmented prognostication in very long-term disorders of consciousness is now required.

Event-related potentials reflect prediction errors and pop-out during comprehension of degraded speech.

Comprehension of degraded speech requires higher-order expectations informed by prior knowledge. Accurate top-down expectations of incoming degraded speech cause a subjective semantic 'pop-out' or conscious breakthrough experience. Indeed, the same stimulus can be perceived as meaningless when no expectations are made in advance. We investigated the event-related potential (ERP) correlates of these top-down expectations, their error signals and the subjective pop-out experience in healthy participants. We manipulated expectations in a word-pair priming degraded (noise-vocoded) speech task and investigated the role of top-down expectation with a between-groups attention manipulation. Consistent with the role of expectations in comprehension, repetition priming significantly enhanced perceptual intelligibility of the noise-vocoded degraded targets for attentive participants. An early ERP was larger for mismatched (i.e. unexpected) targets than matched targets, indicative of an initial error signal not reliant on top-down expectations. Subsequently, a P3a-like ERP was larger to matched targets than mismatched targets only for attending participants-i.e. a pop-out effect-while a later ERP was larger for mismatched targets and did not significantly interact with attention. Rather than relying on complex post hoc interactions between prediction error and precision to explain this apredictive pattern, we consider our data to be consistent with prediction error minimization accounts for early stages of processing followed by Global Neuronal Workspace-like breakthrough and processing in service of task goals.

Strategic and Non-Strategic Semantic Expectations Hierarchically Modulate Neural Processing.

Perception is facilitated by a hierarchy of expectations generated from context and prior knowledge. In auditory processing, violations of local (within-trial) expectations elicit a mismatch negativity (MMN), while violations of global (across-trial) expectations elicit a later positive component (P300). This result is taken as evidence of prediction errors ascending through the expectation hierarchy. However, in language comprehension, there is no evidence that violations of semantic expectations across local-global levels similarly elicit a sequence of hierarchical error signals, thus drawing into question the putative link between event-related potentials (ERPs) and prediction errors. We investigated the neural basis of such hierarchical expectations of semantics in a word-pair priming paradigm. By manipulating the overall proportion of related or unrelated word-pairs across the task, we created two global contexts that differentially encouraged strategic use of primes. Across two experiments, we replicated behavioral evidence of greater priming in the high validity context, reflecting strategic expectations of upcoming targets based on "global" context. In our preregistered EEG analyses, we observed a "local" prediction error ERP effect (i.e., semantic priming) ∼250 ms post-target, which, in exploratory analyses, was followed 100 ms later by a signal that interacted with the global context. However, the later effect behaved in an apredictive manner, i.e., was most extreme for fulfilled expectations, rather than violations. Our results are consistent with interpretations of early ERPs as reflections of prediction error and later ERPs as processes related to conscious access and in support of task demands.

Skipping a Beat: Heartbeat-Evoked Potentials Reflect Predictions during Interoceptive-Exteroceptive Integration.

Several theories propose that emotions and self-awareness arise from the integration of internal and external signals and their respective precision-weighted expectations. Supporting these mechanisms, research indicates that the brain uses temporal cues from cardiac signals to predict auditory stimuli and that these predictions and their prediction errors can be observed in the scalp heartbeat-evoked potential (HEP). We investigated the effect of precision modulations on these cross-modal predictive mechanisms, via attention and interoceptive ability. We presented auditory sequences at short (perceived synchronous) or long (perceived asynchronous) cardio-audio delays, with half of the trials including an omission. Participants attended to the cardio-audio synchronicity of the tones (internal attention) or the auditory stimuli alone (external attention). Comparing HEPs during omissions allowed for the observation of pure predictive signals, without contaminating auditory input. We observed an early effect of cardio-audio delay, reflecting a difference in heartbeat-driven expectations. We also observed a larger positivity to the omissions of sounds perceived as synchronous than to the omissions of sounds perceived as asynchronous when attending internally only, consistent with the role of attentional precision for enhancing predictions. These results provide support for attentionally modulated cross-modal predictive coding and suggest a potential tool for investigating its role in emotion and self-awareness.

Dissociable electrophysiological correlates of semantic access of motor and non-motor concepts.

The notion of semantic embodiment posits that concepts are represented in the same neural sensorimotor systems that were involved in their acquisition. However, evidence in support of embodied semantics - in particular the hypothesised contribution of motor and premotor cortex to the representation of action concepts - is varied. Here, we tested the hypothesis that, consistent with semantic embodiment, sensorimotor cortices will rapidly become active while healthy participants access the meaning of visually-presented motor and non-motor action verbs. Event-related potentials revealed early differential processing of motor and non-motor verbs (164-203 ms) within distinct regions of cortex likely reflecting rapid cortical activation of differentially distributed semantic representations. However, we found no evidence for a specific role of sensorimotor cortices in supporting these representations. Moreover, we observed a later modulation of the alpha band (8-12 Hz) from 555-785 ms over central electrodes, with estimated generators within the left superior parietal lobule, which may reflect post-lexical activation of the object-directed features of the motor action concepts. In conclusion, we find no evidence for a specific role of sensorimotor cortices when healthy participants judge the meaning of visually-presented action verbs. However, the relative contribution of sensorimotor cortices to action comprehension may vary as a function of task goals.

Shining a Light on Awareness: A Review of Functional Near-Infrared Spectroscopy for Prolonged Disorders of Consciousness.

Qualitative clinical assessments of the recovery of awareness after severe brain injury require an assessor to differentiate purposeful behavior from spontaneous behavior. As many such behaviors are minimal and inconsistent, behavioral assessments are susceptible to diagnostic errors. Advanced neuroimaging tools can bypass behavioral responsiveness and reveal evidence of covert awareness and cognition within the brains of some patients, thus providing a means for more accurate diagnoses, more accurate prognoses, and, in some instances, facilitated communication. The majority of reports to date have employed the neuroimaging methods of functional magnetic resonance imaging, positron emission tomography, and electroencephalography (EEG). However, each neuroimaging method has its own advantages and disadvantages (e.g., signal resolution, accessibility, etc.). Here, we describe a burgeoning technique of non-invasive optical neuroimaging-functional near-infrared spectroscopy (fNIRS)-and review its potential to address the clinical challenges of prolonged disorders of consciousness. We also outline the potential for simultaneous EEG to complement the fNIRS signal and suggest the future directions of research that are required in order to realize its clinical potential.

Clinical neurophysiology of prolonged disorders of consciousness: From diagnostic stimulation to therapeutic neuromodulation.

The identification of signs of awareness in patients with prolonged disorders of consciousness (DoC) after severe brain injury is a challenging task for clinicians. Differentiating on behavioural examination the vegetative state (VS) from the minimally conscious state (MCS) can lead to a high misdiagnosis rate. Advanced neuroimaging and neurophysiological techniques can supplement clinical evaluation by providing physiological evidence of brain activity. However, an open issue remains whether these empirical results are directly or indirectly associated with covert consciousness and limitations emerge for their diagnostic application at the single-patient level. On the therapeutic side, the efficacy of both non-invasive and invasive brain stimulation/modulation trials is matter of debate. The present review provides an updated analysis of the diagnostic and prognostic impact that the different neurophysiological techniques of stimulation [including short-latency evoked potentials, long-latency event related potentials (ERPs), transcranial magnetic stimulation (TMS), TMS-EEG co-registration] offer in prolonged DoC. The results of the therapeutic stimulation techniques are also evaluated. It is concluded that TMS-EEG emerges as the most promising tool for differentiating VS from MCS whereas ERPs allow neurophysiologists to probe covert cognitive capacities of each patient. Significant behavioural improvements in prolonged DoC with brain stimulation techniques are still anecdotical and further treatment options are awaited.

Why use a mirror to assess visual pursuit in prolonged disorders of consciousness? Evidence from healthy control participants.

BACKGROUND: Evidence of reliable smooth visual pursuit is crucial for both diagnosis and prognosis in prolonged disorders of consciousness (PDOC). However, a mirror is more likely than an object to elicit evidence of smooth pursuit. Our objective was to identify the physiological and/or cognitive mechanism underlying the mirror benefit. METHODS: We recorded eye-movements while healthy participants simultaneously completed a visual pursuit task and a cognitively demanding two-back task. We manipulated the stimulus to be pursued (two levels: mirror, ball) and the simultaneous cognitive load (pursuit only, pursuit plus two-back task) within subjects. RESULTS: Pursuit of the reflected-own-face in the mirror was associated with briefer fixations that occurred less uniformly across the horizontal plane relative to object pursuit. Secondary task performance did not differ between pursuit stimuli. The secondary task also did not affect eye movement measures, nor did it interact with pursuit stimulus. CONCLUSIONS: Reflected-own-face pursuit is no less cognitively demanding than object pursuit, but it naturally elicits smoother eye movements (i.e. briefer pauses to fixate). A mirror therefore provides greater sensitivity to detect smooth visual pursuit in PDOC because the naturally smoother eye movements may be identified more confidently by the assessor.

A hierarchy of event-related potential markers of auditory processing in disorders of consciousness.

Functional neuroimaging of covert perceptual and cognitive processes can inform the diagnoses and prognoses of patients with disorders of consciousness, such as the vegetative and minimally conscious states (VS;MCS). Here we report an event-related potential (ERP) paradigm for detecting a hierarchy of auditory processes in a group of healthy individuals and patients with disorders of consciousness. Simple cortical responses to sounds were observed in all 16 patients; 7/16 (44%) patients exhibited markers of the differential processing of speech and noise; and 1 patient produced evidence of the semantic processing of speech (i.e. the N400 effect). In several patients, the level of auditory processing that was evident from ERPs was higher than the abilities that were evident from behavioural assessment, indicating a greater sensitivity of ERPs in some cases. However, there were no differences in auditory processing between VS and MCS patient groups, indicating a lack of diagnostic specificity for this paradigm. Reliably detecting semantic processing by means of the N400 effect in passively listening single-subjects is a challenge. Multiple assessment methods are needed in order to fully characterise the abilities of patients with disorders of consciousness.

Somatosensory attention identifies both overt and covert awareness in disorders of consciousness.

OBJECTIVE: Some patients diagnosed with disorders of consciousness retain sensory and cognitive abilities beyond those apparent from their overt behavior. Characterizing these covert abilities is crucial for diagnosis, prognosis, and medical ethics. This multimodal study investigates the relationship between electroencephalographic evidence for perceptual/cognitive preservation and both overt and covert markers of awareness. METHODS: Fourteen patients with severe brain injuries were evaluated with an electroencephalographic vibrotactile attention task designed to identify a hierarchy of residual somatosensory and cognitive abilities: (1) somatosensory steady-state evoked responses, (2) bottom-up attention orienting (P3a event-related potential), and (3) top-down attention (P3b event-related potential). Each patient was also assessed with a clinical behavioral scale and 2 functional magnetic resonance imaging assessments of covert command following. RESULTS: Six patients produced only sensory responses, with no evidence of cognitive event-related potentials. A further 8 patients demonstrated reliable bottom-up attention-orienting responses (P3a). No patient showed evidence of top-down attention (P3b). Only those patients who followed commands, whether overtly with behavior or covertly with functional neuroimaging, also demonstrated event-related potential evidence of attentional orienting. INTERPRETATION: Somatosensory attention-orienting event-related potentials differentiated patients who could follow commands from those who could not. Crucially, this differentiation was irrespective of whether command following was evident through overt external behavior, or through covert functional neuroimaging methods. Bedside electroencephalographic methods may corroborate more expensive and challenging methods such as functional neuroimaging, and thereby assist in the accurate diagnosis of awareness. Ann Neurol 2016;80:412-423.