Multidimensional assessment of heartbeat-evoked responses in disorders of consciousness.

Because consciousness does not necessarily translate into overt behaviour, detecting residual consciousness in noncommunicating patients remains a challenge. Bedside diagnostic methods based on EEG are promising and cost-effective alternatives to detect residual consciousness. Recent evidence showed that the cortical activations triggered by each heartbeat, namely, heartbeat-evoked responses (HERs), can detect through machine learning the presence of minimal consciousness and distinguish between overt and covert minimal consciousness. In this study, we explore different markers to characterize HERs to investigate whether different dimensions of the neural responses to heartbeats provide complementary information that is not typically found under standard event-related potential analyses. We evaluated HERs and EEG average non-locked to heartbeats in six types of participants: healthy state, locked-in syndrome, minimally conscious state, vegetative state/unresponsive wakefulness syndrome, comatose and brain-dead patients. We computed a series of markers from HERs that can generally separate the unconscious from the conscious. Our findings indicate that HER variance and HER frontal segregation tend to be higher in the presence of consciousness. These indices, when combined with heart rate variability, have the potential to enhance the differentiation between different levels of awareness. We propose that a multidimensional evaluation of brain-heart interactions could be included in a battery of tests to characterize disorders of consciousness. Our results may motivate further exploration of markers in brain-heart communication for the detection of consciousness at the bedside. The development of diagnostic methods based on brain-heart interactions may be translated into more feasible methods for clinical practice.

Influence of Heart Rate, Age, and Gender on Heart Rate Variability in Adolescents and Young Adults.

Key autonomic functions are in continuous development during adolescence which can be assessed using the heart rate variability (HRV). However, the influence of different demographic and physiological factors on HRV indices has not been fully explored in adolescents. In this study we aimed to assess the effect of age, gender, and heart rate on HRV indices in two age groups of healthy adolescents (age ranges, 13-16 and 17-20 years) and two groups of healthy young adults (21-24 and 25-30 years). We addressed the issue using 5-min ECG recordings performed in the sitting position in 255 male and female participants. Time, frequency, and informational domains of HRV were calculated. Changes in HRV indices were assessed using a multiple linear regression model to adjust for the effects of heart rate, age, and gender. We found that heart rate produced more significant effects on HRV indices than age or gender. There was a progressive reduction in HRV with increasing age. Sympathetic influence increased with age and parasympathetic influence progressively decreased with age. The influence of gender was manifest only in younger adolescents and young adults. In conclusion, age, gender, and particularly heart rate have a substantial influence on HRV indices, which ought to be considered to avoid biases in the study of the autonomic nervous system development. The lack of the gender-related effects on HRV indices in late adolescence could be related to non-completely achieved maturity of the autonomic mechanisms, which deserves further exploration.

Autonomic impairment of patients in coma with different Glasgow coma score assessed with heart rate variability.

PRIMARY OBJECTIVE: The objective of this study is to assess the functional state of the autonomic nervous system in healthy individuals and in individuals in coma using measures of heart rate variability (HRV) and to evaluate its efficiency in predicting mortality. DESIGN AND METHODS: Retrospective group comparison study of patients in coma classified into two subgroups, according to their Glasgow coma score, with a healthy control group. HRV indices were calculated from 7 min of artefact-free electrocardiograms using the Hilbert-Huang method in the spectral range 0.02-0.6 Hz. A special procedure was applied to avoid confounding factors. Stepwise multiple regression logistic analysis (SMLRA) and ROC analysis evaluated predictions. RESULTS: Progressive reduction of HRV was confirmed and was associated with deepening of coma and a mortality score model that included three spectral HRV indices of absolute power values of very low, low and very high frequency bands (0.4-0.6 Hz). The SMLRA model showed sensitivity of 95.65%, specificity of 95.83%, positive predictive value of 95.65%, and overall efficiency of 95.74%. CONCLUSIONS: HRV is a reliable method to assess the integrity of the neural control of the caudal brainstem centres on the hearts of patients in coma and to predict patient mortality.

Effects of Low-Level Laser Therapy in Autism Spectrum Disorder.

The study examined the efficacy of low-level laser therapy, a form of photobiomodulation, for the treatment of irritability associated with autistic spectrum disorder in children and adolescents aged 5-17 years. Twenty-one of the 40 participants received eight 5-min procedures administered to the base of the skull and temporal areas across a 4-week period (test, i.e., active treatment participants). All the participants were evaluated with the Aberrant Behavior Checklist (ABC), with the global scale and five subscales (irritability/agitation, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech), and the Clinical Global Impressions (CGI) Scale including a severity-of-illness scale (CGI-S) and a global improvement/change scale (CGI-C). The evaluation took place at baseline, week 2 (interim), week 4 (endpoint), and week 8 (post-procedure) of the study. The adjusted mean difference in the baseline to study endpoint change in the ABC irritability subscale score between test and placebo participants was -15.17 in favor of the test procedure group. ANCOVA analysis found this difference to be statistically significant (F = 99.34, p < 0.0001) compared to the baseline ABC irritability subscale score. The study found that low-level laser therapy could be an effective tool for reducing irritability and other symptoms and behaviors associated with the autistic spectrum disorder in children and adolescents, with positive changes maintained and augmented over time.

Very High Frequency Oscillations of Heart Rate Variability in Healthy Humans and in Patients with Cardiovascular Autonomic Neuropathy.

Literature reports on the very high frequency (VHF) range of 0.4-0.9 Hz in heart rate variability (HRV) are scanty. The VHF presence in cardiac transplant patients and other conditions associated with reduced vagal influence on the heart encouraged us to explore this spectral band in healthy subjects and in patients diagnosed with cardiac autonomic neuropathy (CAN), and to assess the potential clinical value of some VHF indices. The study included 80 healthy controls and 48 patients with spinocerebellar ataxia type 2 (SCA2) with CAN. The electrocardiographic recordings of short 5-min duration were submitted to three different spectral analysis methods, including the most generally accepted procedure, and the two novel methods using the Hilbert-Huang transform. We demonstrated the presence of VHF activity in both groups of subjects. However, VHF power spectral density, expressed in relative normalized units, was significantly greater in the SCA2 patients than that in healthy subjects, amounting to 36.1 ± 17.4% vs. 22.9 ± 14.1%, respectively, as also was the instantaneous VHF spectral frequency, 0.58 ± 0.05 vs. 0.64 ± 0.07 Hz, respectively. These findings were related to the severity of CAN. We conclude that VHF activity of HRV is integral to the cardiovascular autonomic control.

Zolpidem efficacy and safety in disorders of consciousness.

Sutton and Clauss presented a detailed review about the effectiveness of zolpidem, discussing recoveries from brain damage due to strokes, trauma and hypoxia. A significant finding has been the unexpected and paradoxical increment of brain activity in vegetative state/unresponsive wakefulness syndrome (VS/UWS). On the contrary, zolpidem is considered one of the best sleep inducers in normal subjects. We have studied series of VS/UWS cases after zolpidem intake. We have demonstrated EEG activation, increment of BOLD signal in different brain regions, and an autonomic influence, mainly characterized by a vagolytic chronotropic effect without a significant increment of the vasomotor sympathetic tone. As this autonomic imbalance might induce cardio- circulatory complications, which we didn't find in any of our patients, we suggest developing future trials under control of physiological indices by bedside monitoring. However, considering that the paradoxical arousing zolpidem effect might be certainly related to brain function improvement, we agree with Sutton and Clauss that future multicentre and multinational clinical trials should be developed, but under control of physiological indices.

Can self-relevant stimuli help assessing patients with disorders of consciousness?

Emotional and self-relevant stimuli are able to automatically attract attention and their use in patients suffering from disorders of consciousness (DOC) might help detecting otherwise hidden signs of cognition. We here recorded EEG in three Locked-in syndrome (LIS) and four Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients while they listened to the voice of a family member or an unfamiliar voice during a passive. Data indicate that, in a passive listening condition, the familiar voice induces stronger alpha desynchronization than the unfamiliar one. In an active condition, the target evoked stronger alpha desynchronization in controls, two LIS patients and one VS/UWS patient. Results suggest that self-relevant familiar voice stimuli can engage additional attentional resources and might allow the detection of otherwise hidden signs of instruction-following and thus residual awareness. Further studies are necessary to find sensitive paradigms that are suited to find subtle signs of cognition and awareness in DOC patients.

Reader Response: Challenges to Brain Death in Revising the Uniform Determination of Death Act: The UDDA Revision Series.

Bernat1 discussed that BD/DNC acceptance has always generated adversaries who, for conceptual or religious reasons, castoff it as human death. Therefore, to provide a conceptual framework of BD/DNC is essential to revise the UDDA.

Zolpidem induces paradoxical metabolic and vascular changes in a patient with PVS.

INTRODUCTION: Zolpidem is a non-benzodiazepine drug used for the therapy of insomnia, which has selectivity for stimulating the effect of GABA-A receptors. Recently, a paradoxical arousing effect of zolpidem in patients with severe brain damage has been repeatedly reported. METHODS: A placebo-controlled magnetic resonance study was conducted to evaluate its effect on BOLD and metabolites spectral signals in a patient with severe brain injuries and an age-matched healthy volunteer. A multi-modal analysis was used to assess aspects in the pharmacologically-induced changes in the resting-state brain metabolism. RESULTS: A significantly increased BOLD signal was transiently localized in the left frontal cortices, bilateral anterior cingulated areas, left thalamus and right head of the caudate nucleus. The healthy subject showed a deactivation of the frontal, parietal and temporal cortices. BOLD signal changes were found to significantly correlate with concentrations of extravascular metabolites in the left frontal cortex. It is discussed that, when zolpidem attaches to modified GABA receptors of neurodormant brain cells, brain activation is induced. This might explain the significant correlations of BOLD signal changes and proton-MRS metabolites in this patient after zolpidem. CONCLUSION: It was concluded that proton-MRS and BOLD signal assessment could be used to study zolpidem-induced metabolic modulation in a resting state.

Reduced Heartbeat-Evoked Responses in a Near-Death Case Report.

BACKGROUND AND PURPOSE: Whether brain-heart communication continues under ventricular fibrillation (VF) remains to be determined. There is weak evidence of physiological changes in cortical activity under VF. Moreover, brain-heart communication has not previously been studied in this condition. We aimed to measure parallel changes in heart-rate variability (HRV), cortical activity, and brain-heart interactions in a patient who experienced VF. METHODS: The EEG and EKG signals for the case report were acquired for approximately 20 h. We selected different 1-min-long segments based on the changes in the EKG waveform. We present the changes in heartbeat-evoked responses (HERs), HRV, and EEG power for each selected segment. RESULTS: The overall physiological activity appeared to deteriorate as VF proceeded. Brain-heart interactions measured using HERs disappeared, with a few aberrant amplitudes appearing occasionally. The parallel changes in EEG and HRV were not pronounced, suggesting the absence of bidirectional neural control. CONCLUSIONS: Our measurements of brain-heart interactions suggested that the evolving VF impairs communication between the central and autonomic nervous systems. These results may support that reduced brain-heart interactions reflect loss of consciousness and deterioration in the overall health state.

Identification and reduction of retained primitive reflexes by sensory stimulation in autism spectrum disorder: effects on qEEG networks and cognitive functions.

Several authors have reported finding retained primitive reflexes (RPRs) in individuals with autism spectrum disorders (ASD). This case report describes the reduction of RPRs and changes in cognitive function after transcutaneous electrical nerve stimulation (TENS) of muscle. Three individuals were examined in a study at the Institute for Neurology and Neurosurgery in Havana, Cuba. Two child neurologists, not involved in the study, conducted clinical examinations on each participant and diagnosed each with ASD based on DSM-V criteria and the Autism Diagnostic Interview-Revised (an autism evaluation tool). Each child with ASD possessed a triad of impairments in three domains: social interaction, communication, and repetitive behaviour. Individuals were evaluated by quantitative electroencephalographic measures and tested by standardised cognitive function tests before and after 12 weeks of intervention. These interventions were associated with reduced ASD symptoms in the three domains, significant changes in qEEG network connectivity and significantly improved performance on standardised cognitive tests.

Short and long term prediction of seizure freedom in drug-resistant focal epilepsy surgery.

BACKGROUND: The selection of candidates for drug-resistant focal epilepsy surgery is essential to achieve the best post-surgical outcomes. OBJECTIVE: To develop two prediction models for seizure freedom in the short and long-term follow-up and from them to create a risk calculator in order to individualize the selection of candidates for surgery and future therapies in each patients. METHODS: A sample of 64 consecutive patients who underwent epilepsy surgery at two Cuban tertiary health institutions between 2012 and 2020 constituted the basis for the prediction models. Two models were obtained through the novel methodology, based on biomarker selection reached by resampling methods, cross-validation and high-accuracy index measured through the area under the receiving operating curve (ROC) procedure. RESULTS: The first, to pre-operative model included five predictors: epilepsy type, seizures per month, ictal pattern, interictal EEG topography and normal or abnormal magnetic resonance imaging,. it's precision was 0.77 at one year, and with four years and more 0.63. The second model including variables from the trans-surgical and post-surgical stages: the interictal discharges in the post-surgical EEG, incomplete or complete resection of the epileptogenic zone, the surgical techniques employed and disappearance of the discharge in post-resection electrocorticography; the precision of this model was 0.82 at one year, and with four years and more 0.97. CONCLUSIONS: The introduction of trans-surgical and post-surgical variables increase the prediction of the pre-surgical model. A risk calculator was developed using these prediction models, which could be useful as an accurate tool to improve the prediction in epilepsy surgery.

The Relationship between Retained Primitive Reflexes and Hemispheric Connectivity in Autism Spectrum Disorders.

BACKGROUND: Autism Spectrum Disorder (ASD) can be identified by a general tendency toward a reduction in the expression of low-band, widely dispersed integrative activities, which is made up for by an increase in localized, high-frequency, regionally dispersed activity. The study assessed ASD children and adults all possessing retained primitive reflexes (RPRs) compared with a control group that did not attempt to reduce or remove those RPRs and then examined the effects on qEEG and brain network connectivity. METHODS: Analysis of qEEG spectral and functional connectivity was performed, to identify associations with the presence or absence of retained primitive reflexes (RPRs), before and after an intervention based on TENS unilateral stimulation. RESULTS: The results point to abnormal lateralization in ASD, including long-range underconnectivity, a greater left-over-right qEEG functional connectivity ratio, and short-range overconnectivity in ASD. CONCLUSIONS: Clinical improvement and the absence of RPRs may be linked to variations in qEEG frequency bands and more optimized brain networks, resulting in more developmentally appropriate long-range connectivity links, primarily in the right hemisphere.

Brain Death Diagnosis in Primary Posterior Fossa Lesions.

Background: New controversies have raised on brain death (BD) diagnosis when lesions are localized in the posterior fossa. Objective: The aim of this study was to discuss the particularities of BD diagnosis in patients with posterior fossa lesions. Materials and Methods: The author made a systematic review of literature on this topic. Results and Conclusions: A supratentorial brain lesion usually produces a rostrocaudal transtentorial brain herniation, resulting in forebrain and brainstem loss of function. In secondary brain lesions (i.e., cerebral hypoxia), the brainstem is also affected like the forebrain. Nevertheless, some cases complaining posterior fossa lesions (i.e., basilar artery thrombotic infarcts, or hemorrhages of the brainstem and/or cerebellum) may retain intracranial blood flow and EEG activity. In this article, I discuss that if a posterior fossa lesion does not produce an enormous increment of intracranial pressure, a complete intracranial circulatory arrest does not occur, explaining the preservation of EEG activity, evoked potentials, and autonomic function. I also addressed Jahi McMath, who was declared braindead, but ancillary tests, performed 9 months after initial brain insult, showed conservation of intracranial structures, EEG activity, and autonomic reactivity to "Mother Talks" stimulus, rejecting the diagnosis of BD. Jahi McMath's MRI study demonstrated a huge lesion in the pons. Some authors have argued that in patients with primary brainstem lesions it might be possible to find in some cases partial recovery of consciousness, even fulfilling clinical BD criteria. This was the case in Jahi McMath.

Retained Primitive Reflexes and Potential for Intervention in Autistic Spectrum Disorders.

We provide evidence to support the contention that many aspects of Autistic Spectrum Disorder (ASD) are related to interregional brain functional disconnectivity associated with maturational delays in the development of brain networks. We think a delay in brain maturation in some networks may result in an increase in cortical maturation and development in other networks, leading to a developmental asynchrony and an unevenness of functional skills and symptoms. The paper supports the close relationship between retained primitive reflexes and cognitive and motor function in general and in ASD in particular provided to indicate that the inhibition of RPRs can effect positive change in ASD.

Cuba's contribution in the diagnosis of brain death/death by neurologic criteria.

I read with interest the paper by Lewis et al. to identify the countries in the Latin America/Caribbean Group of the United Nations (GRULAC) that have protocols for brain death/death by neurologic criteria (BD/DNC). Curiously, the authors don't mention Cuba, which has been one of the most active countries in the area, since the early '90s. The first kidney transplant in Cuba was performed on 24 February 1970, using a cadaveric donor. In September 1992, the First Symposium on Brain Death was held in Havana, with the attendance of the main and world-known authors at that time, like Cristopher Pallis, Earl Walker, among others. These conferences uninterruptedly continued over the years, and the last Symposium was held in December 2018. In the First Symposium, the Cuban Commission for Death Determination presented for the first time the Guidelines for the Determination of BD/DNC in Cuba. Since that time, Machado proposed a concept of death, based on the basic pathophysiological mechanism of consciousness generation. This author also proposed as ancillary tests in BD/DNC diagnosis the use of a test battery composed of multimodality evoked potentials (MEP) and electroretinography (ERG). Later, a Cuban Law for the determination of death was issued. The Cuban Commission The Commission stated that there is only one kind of death, based on the irreversible loss of brain functions based on the whole brain criteria. Furthermore, the Cuban law did not even mention the term 'transplants'. It is clear the human beings die regardless bodies would be useful or not for transplantation.