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Frontiers in Neuroscience 2023The pathological involvement of the central nervous system in SARS-CoV2 (COVID-19) patients is established. The burden of pathology is most pronounced in the brain stem...
The pathological involvement of the central nervous system in SARS-CoV2 (COVID-19) patients is established. The burden of pathology is most pronounced in the brain stem including the medulla oblongata. Hypoxic/ischemic damage is the most frequent neuropathologic abnormality. Other neuropathologic features include neuronophagia, microglial nodules, and hallmarks of neurodegenerative diseases: astrogliosis and microglial reactivity. It is still unknown if these pathologies are secondary to hypoxia versus a combination of inflammatory response combined with hypoxia. It is also unknown how astrocytes react to neuroinflammation in COVID-19, especially considering evidence supporting the neurotoxicity of certain astrocytic phenotypes. This study aims to define the link between astrocytic and microglial pathology in COVID-19 victims in the inferior olivary nucleus, which is one of the most severely affected brain regions in COVID-19, and establish whether COVID-19 pathology is driven by hypoxic damage. Here, we conducted neuropathologic assessments and multiplex-immunofluorescence studies on the medulla oblongata of 18 COVID-19, 10 pre-pandemic patients who died of acute respiratory distress syndrome (ARDS), and 7-8 control patients with no ARDS or COVID-19. The comparison of ARDS and COVID-19 allows us to identify whether the pathology in COVID-19 can be explained by hypoxia alone, which is common to both conditions. Our results showed increased olivary astrogliosis in ARDS and COVID-19. However, microglial density and microglial reactivity were increased only in COVID-19, in a region-specific manner. Also, olivary hilar astrocytes increased YKL-40 (CHI3L1) in COVID-19, but to a lesser extent than ARDS astrocytes. COVID-19 astrocytes also showed lower levels of Aquaporin-4 (AQP4), and Metallothionein-3 in subsets of COVID-19 brain regions. Cluster analysis on immunohistochemical attributes of astrocytes and microglia identified ARDS and COVID-19 clusters with correlations to clinical history and disease course. Our results indicate that olivary glial pathology and neuroinflammation in the COVID-19 cannot be explained solely by hypoxia and suggest that failure of astrocytes to upregulate the anti-inflammatory YKL-40 may contribute to the neuroinflammation. Notwithstanding the limitations of retrospective studies in establishing causality, our experimental design cannot adequately control for factors external to our design. Perturbative studies are needed to confirm the role of the above-described astrocytic phenotypes in neuroinflammation.
PubMed: 37483351
DOI: 10.3389/fnins.2023.1198219 -
Frontiers in Neurology 2022Hypertrophic olivary degeneration (HOD) is a pathology of the inferior olivary nucleus (ION) that occurs after injuries to the Guillain-Mollaret triangle (GMT). Lacking...
PURPOSE
Hypertrophic olivary degeneration (HOD) is a pathology of the inferior olivary nucleus (ION) that occurs after injuries to the Guillain-Mollaret triangle (GMT). Lacking a diagnostic gold standard, diagnosis is usually based on T2 or FLAIR imaging and expert rating. To facilitate precise HOD diagnosis in future studies, we assessed the reliability of this rater-based approach and explored alternative, quantitative analysis.
METHODS
Patients who had suffered strokes in the GMT and a matched control group prospectively underwent an MRI examination including T2, FLAIR, and proton density (PD). Diffusion tensor imaging (DTI) was additionally performed in the patient group. The presence of HOD was assessed on FLAIR, T2, and PD separately by 3 blinded reviewers. Employing an easily reproducible segmentation approach, relative differences in intensity, fractional anisotropy (FA), and mean diffusivity (MD) between both IONs were calculated.
RESULTS
In total, 15 patients were included in this study. The interrater reliability was best for FLAIR, followed by T2 and PD (Fleiss κ = 0.87 / 0.77 / 0.65). The 3 raters diagnosed HOD in 38-46% (FLAIR), 40-47% (T2), and 53-67% (PD) of patients. False-positive findings in the control group were less frequent in T2 than in PD and FLAIR (2.2% / 8.9% / 6.7%). In 53% of patients, the intensity difference between both IONs on PD was significantly increased in comparison with the control group. These patients also showed significantly decreased FA and increased MD.
CONCLUSION
While the rater-based approach yielded the best performance on T2 imaging, a quantitative, more sensitive HOD diagnosis based on ION intensities in PD and DTI imaging seems possible.
PubMed: 35989923
DOI: 10.3389/fneur.2022.950191 -
International Journal of Audiology Sep 2021The medial olivocochlear (MOC) reflex provides efferent feedback from the brainstem to cochlear outer hair cells. Physiologic studies have demonstrated that the MOC...
OBJECTIVE
The medial olivocochlear (MOC) reflex provides efferent feedback from the brainstem to cochlear outer hair cells. Physiologic studies have demonstrated that the MOC reflex is involved in "unmasking" of signals-in-noise at the level of the auditory nerve; however, its functional importance in human hearing remains unclear.
DESIGN
This study examined relationships between pre-neural measurements of MOC reflex strength (click-evoked otoacoustic emission inhibition; CEOAE) and neural measurements of speech-in-noise encoding (speech frequency following response; sFFR) in four conditions (Quiet, Contralateral Noise, Ipsilateral Noise, and Ipsilateral + Contralateral Noise). Three measures of CEOAE inhibition (amplitude reduction, effective attenuation, and input-output slope inhibition) were used to quantify pre-neural MOC reflex strength. Correlations between pre-neural MOC reflex strength and sFFR "unmasking" (i.e. response recovery from masking effects with activation of the MOC reflex in time and frequency domains) were assessed.
STUDY SAMPLE
18 young adults with normal hearing.
RESULTS
sFFR unmasking effects were insignificant, and there were no correlations between pre-neural MOC reflex strength and sFFR unmasking in the time or frequency domain.
CONCLUSION
Our results do not support the hypothesis that the MOC reflex is involved in speech-in-noise neural encoding, at least for features that are represented in the sFFR at the SNR tested.
Topics: Acoustic Stimulation; Cochlea; Efferent Pathways; Humans; Noise; Olivary Nucleus; Otoacoustic Emissions, Spontaneous; Speech
PubMed: 33426967
DOI: 10.1080/14992027.2020.1862425 -
Current Opinion in Neurobiology Oct 2017Artificial intelligence such as deep neural networks exhibited remarkable performance in simulated video games and 'Go'. In contrast, most humanoid robots in the DARPA... (Review)
Review
Artificial intelligence such as deep neural networks exhibited remarkable performance in simulated video games and 'Go'. In contrast, most humanoid robots in the DARPA Robotics Challenge fell down to ground. The dramatic contrast in performance is mainly due to differences in the amount of training data, which is huge and small, respectively. Animals are not allowed with millions of the failed trials, which lead to injury and death. Humans fall only several thousand times before they balance and walk. We hypothesize that a unique closed-loop neural circuit formed by the Purkinje cells, the cerebellar deep nucleus and the inferior olive in and around the cerebellum and the highest density of gap junctions, which regulate synchronous activities of the inferior olive nucleus, are computational machinery for learning from a small sample. We discuss recent experimental and computational advances associated with this hypothesis.
Topics: Animals; Cerebellum; Humans; Machine Learning; Neural Networks, Computer; Neural Pathways; Olivary Nucleus
PubMed: 28841437
DOI: 10.1016/j.conb.2017.07.010 -
The Journal of Comparative Neurology Oct 2023In the brain, microglia are involved in immune responses and synaptic maturation. During early development, these cells invade the brain, proliferate, and...
In the brain, microglia are involved in immune responses and synaptic maturation. During early development, these cells invade the brain, proliferate, and morphologically mature to achieve coverage of the surrounding tissue with their fine processes. Their developmental proliferation overlaps with the postnatal development of neuronal circuits. Within the superior olivary complex (SOC), an auditory brainstem structure, microglia, and their early postnatal development have been documented. A quantification over the full developmental profile of the arrangement and morphological changes in single microglia cells is missing. Here, we used immunofluorescence labeling to quantify their distribution, morphological changes, and coverage during early and late postnatal development in the SOC of Mongolian gerbils. Microglia distributed rather homogenously within each nucleus with a bias to the nucleus borders at postnatal day (P) 5 and more centrally in the nucleus in mature stages. We found a nucleus-specific transient increase in microglia cell number and density reaching its peak at P17 with a subsequent decline to P55 values. Length and branching of microglia protrusions increased especially after P12. The stronger ramification together with the increase in cell density allows coverage of the surrounding tissue from P5 to mature stages, despite the large developmental increase in nucleus size. The transient increase in density during synaptic refinement in SOC nuclei suggests that microglia are important during the pruning period, compensating for developmental increase in tissue volume, and that in mature stages their main function appears tissue surveillance.
PubMed: 37837644
DOI: 10.1002/cne.25547 -
Trends in Cognitive Sciences Jun 2020Cognitively driven pupil modulations reflect certain underlying brain functions. What do these reflections tell us? Here, we review findings that have identified key... (Review)
Review
Cognitively driven pupil modulations reflect certain underlying brain functions. What do these reflections tell us? Here, we review findings that have identified key roles for three neural systems: cortical modulation of the pretectal olivary nucleus (PON), which controls the pupillary light reflex; the superior colliculus (SC), which mediates orienting responses, including pupil changes to salient stimuli; and the locus coeruleus (LC)-norepinephrine (NE) neuromodulatory system, which mediates relationships between pupil-linked arousal and cognition. We discuss how these findings can inform the interpretation of pupil measurements in terms of activation of these neural systems. We also highlight caveats, open questions, and key directions for future experiments for improving these interpretations in terms of the underlying neural dynamics throughout the brain.
Topics: Arousal; Brain; Cognition; Humans; Locus Coeruleus; Pupil
PubMed: 32331857
DOI: 10.1016/j.tics.2020.03.005 -
Frontiers in Neuroscience 2022Melatonin is a transducer of photic environmental information and participates in the synchronization of various physiological and behavioral phenomena. Melatonin can...
Melatonin is a transducer of photic environmental information and participates in the synchronization of various physiological and behavioral phenomena. Melatonin can act directly in several areas of the central nervous system through its membrane receptors coupled to G protein, called MT1 and MT2 receptors. In some structures, such as the retina, hypothalamus and pars tuberalis, the expression of both melatonin receptors shows circadian variations. Melatonin can act in the synchronization of the clock proteins rhythm in these areas. Using the immunohistochemistry technique, we detected the immunoexpression of the melatonin receptors and clock genes clock protein Per1 in the inferior olivary nucleus (ION) of the monkey at specific times of the light-dark phase. The mapping performed by immunohistochemistry showed expressive immunoreactivity (IR) Per1 with predominance during daytime. Both melatonin receptors were expressed in the ION without a day/night difference. The presence of both melatonin receptors and the Per1 protein in the inferior olivary nucleus can indicate a functional role not only in physiological, as in sleep, anxiety, and circadian rhythm, but also a chronobiotic role in motor control mechanisms.
PubMed: 36605547
DOI: 10.3389/fnins.2022.1072772 -
Neuroscience May 2021As a tribute to Masao Ito, we propose a model of cerebellar learning that incorporates and extends his original model. We suggest four principles that align well with... (Review)
Review
As a tribute to Masao Ito, we propose a model of cerebellar learning that incorporates and extends his original model. We suggest four principles that align well with conclusions from multiple cerebellar learning systems. (1) Climbing fiber inputs to the cerebellum drive early, fast, poorly-retained learning in the parallel fiber to Purkinje cell synapse. (2) Learned Purkinje cell outputs drive late, slow, well-retained learning in non-Purkinje cell inputs to neurons in the cerebellar nucleus, transferring learning from the cortex to the nucleus. (3) Recurrent feedback from Purkinje cells to the inferior olive, through interneurons in the cerebellar nucleus, limits the magnitude of fast, early learning in the cerebellar cortex. (4) Functionally different inputs are subjected to plasticity in the cerebellar cortex versus the cerebellar nucleus. A computational neural circuit model that is based on these principles mimics a large amount of neural and behavioral data obtained from the smooth pursuit eye movements of monkeys.
Topics: Animals; Cerebellar Nuclei; Cerebellum; Olivary Nucleus; Purkinje Cells; Pursuit, Smooth
PubMed: 32866603
DOI: 10.1016/j.neuroscience.2020.08.026 -
Neural Networks : the Official Journal... Nov 2022The inferior olivary (IO) nucleus makes up the signal gateway for several organs to the cerebellar cortex. Located within the sensory-motor-cerebellum pathway, the IO...
The inferior olivary (IO) nucleus makes up the signal gateway for several organs to the cerebellar cortex. Located within the sensory-motor-cerebellum pathway, the IO axons, i.e., climbing fibres (CFs), massively synapse onto the cerebellar Purkinje cells (PCs) regulating motor learning whilst the olivary nucleus receives negative feedback through the GABAergic nucleo-olivary (NO) pathway. The NO pathway regulates the electrical coupling (EC) amongst the olivary cells thus facilitating synchrony and timing. However, the involvement of this EC regulation on cerebellar adaptive behaviour is still under debate. In our study we have used a spiking cerebellar model to assess the role of the NO pathway in regulating vestibulo-ocular-reflex (VOR) adaptation. The model incorporates spike-based synaptic plasticity at multiple cerebellar sites and an electrically-coupled olivary system. The olivary system plays a central role in regulating the CF spike-firing patterns that drive the PCs, whose axons ultimately shape the cerebellar output. Our results suggest that a systematic GABAergic NO deactivation decreases the spatio-temporal complexity of the IO firing patterns thereby worsening the temporal resolution of the olivary system. Conversely, properly coded IO spatio-temporal firing patterns, thanks to NO modulation, finely shape the balance between long-term depression and potentiation, which optimises VOR adaptation. Significantly, the NO connectivity pattern constrained to the same micro-zone helps maintain the spatio-temporal complexity of the IO firing patterns through time. Moreover, the temporal alignment between the latencies found in the NO fibres and the sensory-motor pathway delay appears to be crucial for facilitating the VOR. When we consider all the above points we believe that these results predict that the NO pathway is instrumental in modulating the olivary coupling and relevant to VOR adaptation.
Topics: Action Potentials; Olivary Nucleus; Purkinje Cells; Cerebellum; Synapses
PubMed: 36116334
DOI: 10.1016/j.neunet.2022.08.020 -
BMJ Case Reports Jul 2017
Topics: Adult; Brain Diseases; Humans; Hypertrophy; Incidental Findings; Male; Olivary Nucleus
PubMed: 28754749
DOI: 10.1136/bcr-2017-220212