Brainstem Function Research Articles

The pain conductor: brainstem modulation in acute and chronic pain.

It is well established in experimental settings that brainstem circuits powerfully modulate the multidimensional experience of pain. This review summarizes current understanding of the roles of brainstem nuclei in modulating the intensity of pain, and how these circuits might be recruited therapeutically for pain relief in chronic and palliative settings. The development of ultra-high field magnetic resonance imaging and more robust statistical analyses has led to a more integrated understanding of brainstem function during pain. It is clear that a number of brainstem nuclei and their overlapping pathways are recruited to either enhance or inhibit incoming nociceptive signals. This review reflects on early preclinical research, which identified in detail brainstem analgesic function, putting into context contemporary investigations in humans that have identified the role of specific brainstem circuits in modulating pain, their contribution to pain chronicity, and even the alleviation of palliative comorbidities. The brainstem is an integral component of the circuitry underpinning pain perception. Enhanced understanding of its circuitry in experimental studies in humans has, in recent years, increased the possibility for better optimized pain-relief strategies and the identification of vulnerabilities to postsurgical pain problems. When integrated into the clinical landscape, these experimental findings of brainstem modulation of pain signalling have the potential to contribute to the optimization of pain management and patient care from acute, to chronic, to palliative states.

The "Primitive Brain Dysfunction" Theory of Autism: The Superior Colliculus Role.

A better understanding of the pathogenesis of autism will help clarify our conception of the complexity of normal brain development. The crucial deficit may lie in the postnatal changes that vision produces in the brainstem nuclei during early life. The superior colliculus is the primary brainstem visual center. Although difficult to examine in humans with present techniques, it is known to support behaviors essential for every vertebrate to survive, such as the ability to pay attention to relevant stimuli and to produce automatic motor responses based on sensory input. From birth to death, it acts as a brain sentinel that influences basic aspects of our behavior. It is the main brainstem hub that lies between the environment and the rest of the higher neural system, making continuous, implicit decisions about where to direct our attention. The conserved cortex-like organization of the superior colliculus in all vertebrates allows the early appearance of primitive emotionally-related behaviors essential for survival. It contains first-line specialized neurons enabling the detection and tracking of faces and movements from birth. During development, it also sends the appropriate impulses to help shape brain areas necessary for social-communicative abilities. These abilities require the analysis of numerous variables, such as the simultaneous evaluation of incoming information sustained by separate brain networks (visual, auditory and sensory-motor, social, emotional, etc.), and predictive capabilities which compare present events to previous experiences and possible responses. These critical aspects of decision-making allow us to evaluate the impact that our response or behavior may provoke in others. The purpose of this review is to show that several enigmas about the complexity of autism might be explained by disruptions of collicular and brainstem functions. The results of two separate lines of investigation: 1. the cognitive, etiologic, and pathogenic aspects of autism on one hand, and two. the functional anatomy of the colliculus on the other, are considered in order to bridge the gap between basic brain science and clinical studies and to promote future research in this unexplored area.

Corticofugal and Brainstem Functions Associated With Medial Olivocochlear Cholinergic Transmission.

Cholinergic transmission is essential for survival and reproduction, as it is involved in several physiological responses. In the auditory system, both ascending and descending auditory pathways are modulated by cholinergic transmission, affecting the perception of sounds. The auditory efferent system is a neuronal network comprised of several feedback loops, including corticofugal and brainstem pathways to the cochlear receptor. The auditory efferent system’s -final and mandatory synapses that connect the brain with the cochlear receptor- involve medial olivocochlear neurons and outer hair cells. A unique cholinergic transmission mediates these synapses through α9/α10 nicotinic receptors. To study this receptor, it was generated a strain of mice carrying a null mutation of the Chrna9 gene (α9-KO mice), lacking cholinergic transmission between medial olivocochlear neurons and outer hair cells, providing a unique opportunity to study the role of medial olivocochlear cholinergic transmission in auditory and cognitive functions. In this article, we review behavioral and physiological studies carried out to research auditory efferent function in the context of audition, cognition, and hearing impairments. Auditory studies have shown that hearing thresholds in the α9-KO mice are normal, while more complex auditory functions, such as frequency selectivity and sound localization, are altered. The corticofugal pathways have been studied in α9-KO mice using behavioral tasks, evidencing a reduced capacity to suppress auditory distractors during visual selective attention. Finally, we discuss the evolutionary role of the auditory efferent system detecting vocalizations in noise and its role in auditory disorders, such as the prevention of age-related hearing loss.

Rethinking Brain Death: A Physiological, Philosophical and Ethical Approach

The term ‘brain death’ is a rather untenable description to be defended ethically. This needs to be sorted out to ‘cortical brain death’, ‘whole brain death’ and WBD should include the brainstem. Organ transplants confound the difference between WBD and ‘biological death’, that is, the complete cessation of body function. It is clearly an ethical issue of taking a life, however, I argue for the greater good, IF it is clearly documented that irreversibility presents itself through multiple criteria (apnea, brainstem function, lack of long onset EEG, etc.). If meeting these criteria, we can have medical, physiological and moral standards and it is ethical to declare brain death, thus allowing organ transplants, and by definition, create biological death by doing so. This is a very consequentialist approach, but it does appease the dualistic ethics by separating the brain, or, more to the point, the concept of the ‘conscience’, and the possibility of defining ‘personhood’ or lack thereof. I believe the 1968 Harvard ‘declaration of death’ doesn’t fit the above criteria and the AMA declaration (formally adopted in 2003) states that: “a determination of death must be made in accordance with accepted medical standards”, however, those medical standards were not described. This paper addresses those standards.

Brainstem auditory evoked potential in cognitive impairment in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) can cause mild cognitive impairment (MCI) which threatens the health of patients. So the diagnosis of MCI is particularly important. It is reported that brainstem auditory evoked potential (BAEP) is a sensitive tool to detect the brainstem function in patients with T2DM. This study aimed to investigate the relationship between BAEP and MCI in patients with T2DM. A total of 244 T2DM patients with normal hearing, including 117 normal cognition patients and 127 MCI patients, were recruited in this cross-sectional study. Each subject underwent the BAEP examination. The diagnosis of MCI was based on the diagnostic guideline developed by the National Institute on Aging-Alzheimer's Association workgroups. The Montreal Cognitive Assessment (MoCA) was used to assess the cognitive function of the subjects. Compared with the normal cognition group, the patients in the MCI group had longer latencies of waves III and V and interpeak latencies (IPL) I-V in both ears (P<0.05). The significant negative correlations were found between the latencies of waves III, V, IPL I-V, and MoCA score in both ears (P<0.05). Logistic regression showed that the prolongations of latunits of waves III and V and IPL I-V in both ears were still associated with MCI after adjustment for mixed factors (P<0.05). These results indicate abnormal auditory pathway in brainstem of T2DM patients with MCI. BAEP may contribute to the clinical diagnosis of MCI in patients with T2DM.

Evaluation of the Auditory System in Autistic Children Using Evoked Otoacoustic Emissions and a Contralateral Suppression Test.

In this study, we evaluated the cochlea, medial olivocochlear system, and brainstem function in autistic children using evoked otoacoustic emissions (OAEs) and a noninvasive contralateral suppression (CLS) test. In total, we included 21 autistic children with normal hearing (study group) and 11 healthy children (control group). Transient-evoked OAEs (TEOAEs) and CLS of TEOAE were evaluated in the left and right ears of all patients. In a silent room, spontaneous, transient, and dP ILO292 were evaluated. The mean age of the study and control group was 9.1 years (range: 6-13 and 6-12 years, respectively). For the study group, there was no statistically significant difference between the OAE and CLS values of the right ear (P > .05). However, for the left ears, OAE values were statistically significantly higher than the CLS values (P < .05). In the control group, the OAE values of both ears were statistically significantly higher than the CLS values (P < .05). In autistic children with normal hearing, the medial olivocochlear system functions more effectively in the right ear than the left ear. Asymmetry between the ears islikely responsible for the peripheral auditory lateralization and independence in auditory function between the left and rightears.

Neurological pupil index during cardiopulmonary resuscitation is associated with admission to ICU in non-traumatic out-of-hospital cardiac arrest patients

Pupillary light reflex (PLR) is a simple method to assess brainstem function and can be measured objectively and accurately using pupillometry. We sought to investigate the relationship between PLR measured with pupillometry during cardiopulmonary resuscitation (CPR) and early prognosis of out-of-hospital cardiac arrest (OHCA) patients. This study was a single-centre prospective observational study. All OHCA patients who received CPR in the emergency department (ED) from August 2019 to January 2021 were registered, and adult patients whose neurological pupil index (NPi) was measured with an automated pupillometer during CPR in the ED were included. The primary outcome was admission to the intensive care unit (ICU). A total of 109 patients were included, and the mean of the NPi measurements of all the patients was 0.1 ± 0.7. The mean of the NPi was higher in the patients admitted to the ICU than in those who died in the ED, 0.5 ± 1.2 vs. 0.0 ± 0.1 (p = 0.031). Receiver operating characteristic analysis was performed to determine the cut-off value of the NPi, and the optimal cut-off value for ICU admission was 2.0 with sensitivity and specificity 0.769 and 0.652, respectively. Patients with NPi &gt;2.0 showed higher rates of admission to ICU, ICU survival, and good neurologic outcomes at hospital discharge and at 3 months following cardiac arrest, than the patients with NPi ≤2.0. Firth’s bias-reduced penalised-likelihood multivariable logistic regression analysis showed that the odds ratio of the group with NPi &gt;2.0 was 14.37 (95% confidence interval, 1.80–179.12), which was an independent variable associated with admission to ICU. NPi of higher than 2.0 is one of the indicators associated with an early favourable outcome of OHCA patients.

Visualization of Brainstem Function in Brainstem Cavernous Hemangioma Surgery and Its Application to Intraoperative Manipulation

Visualization of Brainstem Function in Brainstem Cavernous Hemangioma Surgery and Its Application to Intraoperative Manipulation

EUTHANASIA AND ISLAMIC RULINGS PERTINENT TO MAINTAINING AND REMOVING ARTIFICIAL LIFE SUPPORT DEVICES

This paper is intended to elaborate on the legal ruling of removing life support from a brain-dead person. Brain death means the permanent absence of brainstem and cerebral functions, not only the death of the brain cortex. Life support devices restore the functions of the heart and respiratory system, which sometimes result in the full recovery of consciousness of the patient and all of his basic functions. It is possible for the patient to restore normal breathing and leave the hospital in a full healthy state. On this basis, it is not permissible for a doctor to remove these devices before the brainstem dies, otherwise this would cause a real and irreversible death of the patient. In this case, the doctor bears full civil and criminal responsibility. The doctor is held accountable if he refrains from providing assistance to this patient who is legally and medically alive. It is permissible to remove artificial life devices once the death of the brain is ascertained in the light of the above-mentioned diagnoses. Then, the patient will be transferred to another room, but his death is announced only after the heart stops functioning. It is from this moment that the rulings of death are applied. The responsibility of removing these devices and declaring death is the work of a specialized medical committee that approves the diagnosis and issues a burial permit.

Restoring Shank3 in the rostral brainstem of shank3ab\u2212/\u2212 zebrafish autism models rescues sensory deficits

People with Phelan-McDermid Syndrome, caused by mutations in the SHANK3 gene, commonly exhibit reduced responses to sensory stimuli; yet the changes in brain-wide activity that link these symptoms to mutations in the shank3 gene remain unknown. Here we quantify movement in response to sudden darkness in larvae of two shank3 zebrafish mutant models and show that both models exhibit dampened responses to this stimulus. Using brain-wide activity mapping, we find that shank3−/− light-sensing brain regions show normal levels of activity while sensorimotor integration and motor regions are less active. Specifically restoring Shank3 function in a sensorimotor nucleus of the rostral brainstem enables the shank3−/− model to respond like wild-type. In sum, we find that reduced sensory responsiveness in shank3−/− models is associated with reduced activity in sensory processing brain regions and can be rescued by restoring Shank3 function in the rostral brainstem. These studies highlight the importance of Shank3 function in the rostral brainstem for integrating sensory inputs to generate behavioral adaptations to changing sensory stimuli.

Diagnostic accuracy of brain stem auditory evoked response in distinguishing drug-induced parkinsonism from Parkinson'sdisease

ObjectivesBrainstem auditory evoked response (BAER) is a non-invasive modality that can be used to investigate brainstem neuronal function in movement disorders. The differentiation between drug-induced parkinsonism (DIP) and Parkinson's disease (PD) can be very challenging. Although PD and DIP to some extent display similar clinical symptoms, the underlying pathophysiologic mechanisms are entirely different. Given these differences in pathogenesis, and the diagnostic utility of BAER for detecting brainstem function, BAER may help to distinguish between PD and DIP. This study aimed to assess the accuracy and predictive values of BAER parameters in differentiating DIP from PD. MethodsWe prospectively studied143 participants classified within three groups, including 50 controls, 57 PD, and 36 DIP. BAER was performed on all patients in the study. Patients in the DIP group were followed up for at least one year after discontinuation of the causative drug and examined for final diagnosis. We compared BAER latencies of the three groups and measured sensitivity, specificity, predictive values, likelihood ratios, and accuracy of BAER in diagnosing DIP. ResultWaves V, I-V, and III-V latencies were significantly prolonged among the PD patients compared to the DIP and the control group; however, there were no significant differences in BAER latencies between the DIP and the control group. Waves V and I-V latencies revealed the highest accuracy (86% and 79%, respectively) in distinguishing DIP from PD with high negative predictive value(89% and 83%, respectively) as well as a high negative likelihood ratio (0.2and 0.3, respectively). ConclusionThis study showed that waves V and I-V latencies are significantly prolonged in PD patients compared to those with DIP, consistent with the proposed mechanisms of neurodegeneration in PD, particularly in the midbrain and pons. Consequently, BAER could be used as a useful diagnostic tool for differentiating DIP from PD.

The effect of Glibenclamide on somatosensory evoked potentials after cardiac arrest in rats.

Science continues to search for a neuroprotective drug therapy to improve outcomes after cardiac arrest (CA). The use of glibenclamide (GBC) has shown promise in preclinical studies, but its effects on neuroprognostication tools are not well understood. We aimed to investigate the effect of GBC on somatosensory evoked potential (SSEP) waveform recovery post CA and how this relates to the early prediction of functional outcome, with close attention to arousal and somatosensory recovery, in a rodent model of CA. Sixteen male Wistar rats were subjected to 8-min asphyxia CA and assigned to GBC treatment (n = 8) or control (n = 8) groups. GBC was administered as a loading dose of 10μg/kg intraperitoneally 10min after the return of spontaneous circulation, followed by a maintenance dosage of 1.6μg/kg every 8h for 24h. SSEPs were recorded from baseline until 150min following CA. Coma recovery, arousal, and brainstem function, measured by subsets of theneurological deficit score (NDS), werecompared between both groups. SSEP N10 amplitudes were compared between the two groups at 30, 60, 90, and 120min post CA. Rats treated with GBC had higher sub-NDS scores post CA, with improved arousal and brainstem function recovery (P = 0.007). Both groups showed a gradual improvement of SSEP N10 amplitude over time, from 30 to 120min post CA. Rats treated with GBC showed significantly better SSEP recovery at every time point (P < 0.001 for 30, 60, and 90min; P = 0.003 for 120min). In the GBC group, the N10 amplitude recovered to baseline by 120min post CA. Quantified Cresyl violet staining revealed a significantly greater percentage of damage in the control group compared with the GBC treatment group (P=0.004). Glibenclamide improves coma recovery, arousal, and brainstem function after CA with decreased number of ischemic neurons in a rat model. GBC improves SSEP recovery post CA, with N10 amplitude reaching the baseline value by 120min, suggesting early electrophysiologic recovery with this treatment. This medication warrants further exploration as a potential drug therapy to improve functional outcomes in patients after CA.

Effects of transcranial ultrasound stimulation on trigeminal blink reflex excitability

Recent evidence indicates that transcranial ultrasound stimulation (TUS) modulates sensorimotor cortex excitability. However, no study has assessed possible TUS effects on the excitability of deeper brain areas, such as the brainstem. In this study, we investigated whether TUS delivered on the substantia nigra, superior colliculus, and nucleus raphe magnus modulates the excitability of trigeminal blink reflex, a reliable neurophysiological technique to assess brainstem functions in humans.

Brainstem Auditory Impairment in Very Preterm Infants who Experience Chronic Sublethal Hypoxia

Very preterm infants who suffer from bronchopulmonary dysplasia (BPD), a major neonatal complication, often experience frequent episodes of hypoxaemia or prolonged hypoxaemia, resulting in significant chronic sublethal hypoxia (CSH). Whether the CSH occurring during the neonatal period exerts any adverse effect on the immature brainstem auditory system remains a topic of attracting considerable interest. With brainstem auditory evoked response (BAER) and particularly maximum length sequence (MLS) BAER, recent investigators have revealed that neonatal BPD damages functional integrity of the immature brainstem auditory system. There are significant abnormalities in the BAER components that reflect central neural function of the auditory brainstem. By comparison, there are only mild abnormalities in the BAER components that reflect peripheral neural function of the auditory brainstem. Clearly, CSH associated with neonatal BPD damage central neural conduction, suggesting impaired myelination and synaptic dysfunction, in the immature auditory brainstem, but exerts limited effect on peripheral neural function of the brainstem. These abnormalities tended to be improved after term date. CSH occurring during the neonatal period damages myelination of the central auditory system, which tends to be alleviated after term date.

Auditory brainstem response: An overview of neurophysiological implications and clinical applications -A Narrative Review.

Evoked Potentials are electrical potentials that occur in a group of neurons in response to stimulation of a sensory organ which can be recorded by surface electrodes. Testing evoked potentials is useful in assessing the integrity of neuronal pathways both at sensory and motor levels of neural control. Early auditory evoked potentials include cochlear and brainstem auditory-evoked potentials, popularly known as electrocochleogram, and auditory brainstem response. Evoked potential audiometry is a neurophysiogical test to assess auditory pathway function in response to auditory stimuli. Auditory brainstem response mainly assesses brainstem functions and integrity. These evoked potentials are widely used for assessment of the cochlear functions, auditory nerve and the brainstem. Most common indications for auditory evoked potentials include routine newborn hearing screening for auditory pathway deficits, detecting retrocochlear pathologies, intraoperative and intensive care monitoring, frequency-related measurement of auditory sensitivity and for diagnosing some demyelinating disorders in initial stages. The current narrative review was planned to highlight auditory brainstem response recording's basic principles, uses and methods of interpretation in health and disease phases.

Neurological Determination of Death Following Infratentorial Stroke: A Population-Based Cohort Study.

There is international variability in whether neurological determination of death (NDD) is conceptually defined based on permanent loss of brainstem function or "whole brain death." Canadian guidelines are not definitive. Patients with infratentorial stroke may meet clinical criteria for NDD despite persistent cerebral blood flow (CBF) and relative absence of supratentorial injury. We performed a multicenter cohort study involving patients that died from ischemic or hemorrhagic stroke in Alberta intensive care units from 2013 to 2019, focusing on those with infratentorial involvement. Medical records were reviewed to determine the incidence and proportion of patients that met clinical criteria for NDD; whether ancillary testing was performed; and if so, whether this demonstrated the absence of CBF. There were 95 (27%) deaths from infratentorial and 263 (73%) from supratentorial stroke. Sixteen patients (17%) with infratentorial stroke had neurological examination consistent with NDD (0.55 cases per million per year). Among patients that underwent confirmatory evaluation for NDD with an apnea test, ancillary test (radionuclide scan), or both, ancillary testing was more common with infratentorial compared with supratentorial stroke (10/12 (85%) vs. 25/47 (53%), p = 0.04). Persistent CBF was detected in 6/10 (60%) patients with infratentorial compared with 0/25 with supratentorial stroke (p = 0.0001). Infratentorial stroke leading to clinical criteria for NDD occurs with an annual incidence of about 0.55 per million. There is variability in clinicians' use of ancillary testing. Persistent CBF was detected in more than half of patients that underwent radionuclide scans. Canadian consensus is needed to guide clinical practice.

Ping-pong gaze in a refractory focal status epilepticus

An 83-year-old woman presented to emergency department with fever, low level of consciousness and right deviation in the conjugate gaze. Neurological examination revealed a spontaneous, slow, horizontal and continuous conjugate eye deviation alternating every 2 to 3 seconds. An electroencephalogram revealed periodic paroxysmal activity with a frequency of 2-3 Hz in left frontal hemispheric. Neuroimaging didn’t show pathological findings. Polymorphonuclear leukocytes were observed in CSF without evidence of microorganisms. Antiepileptic therapy was started without improvement. Finally, the patient died because of refractory focal status. Ping Pong Gaze (PPG) is a slow and rhythmical horizontal abnormal eye movement with a fixed frequency that is observed in comatose states and indicates diffuse structural brain lesions with preserved brainstem functions. PPG presence is an indicator of bad prognosis. We describe a PPG case with a synchronous eye movement with the electroencephalogram activity. Keywords: Ping-pong gaze; status epilepticus; electroencephalography; epilepsy; seizure.

A comparative analysis of the modified Rankin Scale, Karnofsky Performance Status and Kurtzke expanded disability status scale in the perioperative management of patients with brainstem cavernous malformations

BackgroundThe neurological conditions of brainstem cerebral cavernous malformation (BCM) patients are usually ascertained using Karnofsky Performance Status (KPS) or the modified Rankin scale (mRS). However, these scales do not reflect slight changes in brainstem function, because neither KPS nor mRS includes brainstem symptoms such as worsening of swallowing or diplopia. The main problem when managing the BCM patients is that we can neither systematically record neurological changes nor conduct clinical outcome investigations of BCM due to the lack of an adequately detailed assessment system. PurposeWe investigated the usefulness of the Kurtzke expanded disability status scale (EDSS), which is already in widespread clinical use for multiple sclerosis because it provides certainty in evaluating brainstem symptoms. MethodsWe retrospectively analyzed neurological transitions in surgical BCM cases using the modified Rankin scale (mRS), Karnofsky performance status (KPS), and EDSS. We compared each neurological score transition, and determined which scale allows the most accurate recording of neurological changes in patients. ResultsWe proposed lesion removal for patients who showed both neurological deterioration and lesion enlargement caused by re-bleeding, and the surgery was accepted by 10 patients. EDSS allowed us to assess patient status more accurately than KPS or mRS particularly during the perioperative period. In the statistical analysis, only EDSS differed significantly during the period between the initial proposal of surgery and the immediate preoperative period. ConclusionOur results suggest EDSS to be superior for managing BCM patients, as compared to KPS and mRS. Thus, EDSS may serve as an alternative scale for assessing BCM patients.

Rescuing Auditory Temporal Processing with a Novel Augmented Acoustic Environment in an Animal Model of Congenital Hearing Loss.

Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by hearing loss that is not assessed on standard audiological examinations, such as reduced temporal processing acuity. To assess whether sound therapy may improve these deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. The DBA/2J mouse strain develops rapid, base to apex, progressive SNHL beginning at birth and is functionally deaf by six months of age. Hearing sensitivity and auditory brainstem function was measured using otoacoustic emissions, auditory brainstem response (ABR) and extracellular recording from the inferior colliculus (IC) in mice following exposure to 30 d of continuous AAE. Peripheral function and sound sensitivity in auditory midbrain neurons improved following exposure to both types of AAE. However, exposure to a novel, temporally complex AAE more strongly improved a measure of temporal processing acuity, neural gap-in-noise detection in the auditory midbrain. These experiments suggest that targeted sound therapy may be harnessed to improve hearing outcomes for children suffering from congenital SNHL.

Early diagnosis of mortality using admission CT perfusion in severe traumatic brain injury patients (ACT-TBI): protocol for a prospective cohort study

IntroductionSevere traumatic brain injury (TBI) is a catastrophic neurological condition with significant economic burden. Early in-hospital mortality (<48 hours) with severe TBI is estimated at 50%. Several clinical examinations exist...