Heterogeneous Ca2+ influx along the adult calyx of held: a structural and computational study

The calyx of Held is a morphologically complex nerve terminal containing hundreds to thousands of active zones. The calyx must support high rates of transient, sound-evoked vesicular release superimposed on a background of sustained release, due to the high spontaneous rates of some afferent fibers. One means of distributing vesicle release in space and time is to have heterogeneous release probabilities (Pr) at distinct active zones, which has been observed at several CNS synapses including the calyx of Held. Pr may be modulated by vesicle proximity to Ca2+ channels, by Ca2+ buffers, by changes in phosphorylation state of proteins involved in the release process, or by local variations in Ca2+ influx. In this study, we explore the idea that the complex geometry of the calyx also contributes to heterogeneous Pr by impeding equal propagation of action potentials through all calyx compartments. Given the difficulty of probing ion channel distribution and recording from adult calyces, we undertook a structural and modeling approach based on computerized reconstructions of calyces labeled in adult cats. We were thus able to manipulate placement of conductances and test their effects on Ca2+ concentration in all regions of the calyx following an evoked action potential in the calyceal axon. Our results indicate that with a non-uniform distribution of Na+ and K+ channels, action potentials do not propagate uniformly into the calyx, Ca2+ influx varies across different release sites, and latency for these events varies among calyx compartments. We suggest that the electrotonic structure of the calyx of Held, which our modeling efforts indicate is very sensitive to the axial resistivity of cytoplasm, may contribute to variations in release probability within the calyx.     

Early weaning induces anxiety and precocious myelination in the anterior part of the basolateral amygdala of male Balb/c mice

Weaning is one of the most important events that occur during the early stages of life. For example, precocious weaning is known to increase anxiety-related behaviors in rodents. Here, we demonstrate that in addition to increasing anxiety, early-weaning manipulations alter the accumulation of galactosylceramide, a specific myelin constituent, and the axonal structure of myelinated fibers in the amygdala of male Balb/c mice. We found that early-weaned male mice entered the open arms of an elevated plus-maze less frequently than normally weaned mice at 3 and 5 weeks of age, which indicates persistently higher anxiety levels. However, early-weaned females exhibited fewer entries into the open arms only at 5 weeks of age. Lipid analysis of mice amygdalas showed the early accumulation of galactosylceramide in early-weaned male, but not female, mice at 5 weeks. The precocious accumulation of galactosylceramide was observed only in the amygdala; galactosylceramide accumulation was not observed in the prefrontal cortex or hippocampus of early-weaned male mice. Electron microscopy showed an increase in the number and a decrease in the diameter of myelinated axons in the anterior part of the basolateral amygdala in early-weaned male mice at 5 weeks. These results suggest that the higher anxiety levels observed in early-weaned male mice could be related to precocious myelin formation in the anterior part of the basolateral amygdala.     

Psychedelics and music: neuroscience and therapeutic implications

Abstract

From the beginning of therapeutic research with psychedelics, music listening has been consistently used as a method to guide or support therapeutic experiences during the acute effects of psychedelic drugs. Recent findings point to the potential of music to support meaning-making, emotionality, and mental imagery after the administration of psychedelics, and suggest that music plays an important role in facilitating positive clinical outcomes of psychedelic therapy. This review explores the history of, contemporary research on, and future directions regarding the use of music in psychedelic research and therapy, and argues for more detailed and rigorous investigation of the contribution of music to the treatment of psychiatric disorders within the novel framework of psychedelic therapy.     

Brain Tumor Networks in Diffuse Glioma

Diffuse gliomas are primary brain tumors associated with a poor prognosis. Cellular and molecular mechanisms driving the invasive growth patterns and therapeutic resistance are incompletely understood. The emerging field of cancer neuroscience offers a novel approach to study these brain tumors in the context of their intricate interactions with the nervous system employing and combining methodological toolsets from neuroscience and oncology. Increasing evidence has shown how neurodevelopmental and neuronal-like mechanisms are hijacked leading to the discovery of multicellular brain tumor networks. Here, we review how gap junction-coupled tumor-tumor-astrocyte networks, as well as synaptic and paracrine neuron-tumor networks drive glioma progression. Molecular mechanisms of these malignant, homo- and heterotypic networks, and their complex interplay are reviewed. Lastly, potential clinical-translational implications and resulting therapeutic strategies are discussed.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01320-w.     

Brief Report: Bias in machine learning models can be significantly mitigated by careful training: Evidence from neuroimaging studies

Despite the great promise that machine learning has offered in many fields of medicine, it has also raised concerns about potential biases and poor generalization across genders, age distributions, races and ethnicities, hospitals, and data acquisition equipment and protocols. In the current study, and in the context of three brain diseases, we provide evidence which suggests that when properly trained, machine learning models can generalize well across diverse conditions and do not necessarily suffer from bias. Specifically, by using multistudy magnetic resonance imaging consortia for diagnosing Alzheimer’s disease, schizophrenia, and autism spectrum disorder, we find that well-trained models have a high area-under-the-curve (AUC) on subjects across different subgroups pertaining to attributes such as gender, age, racial groups and different clinical studies and are unbiased under multiple fairness metrics such as demographic parity difference, equalized odds difference, equal opportunity difference, etc. We find that models that incorporate multisource data from demographic, clinical, genetic factors, and cognitive scores are also unbiased. These models have a better predictive AUC across subgroups than those trained only with imaging features, but there are also situations when these additional features do not help.     

Automated and manual segmentation of the hippocampus in human infants

The hippocampus, critical for learning and memory, undergoes substantial changes early in life. Investigating the developmental trajectory of hippocampal structure and function requires an accurate method for segmenting this region from anatomical MRI scans. Although manual segmentation is regarded as the “gold standard” approach, it is laborious and subjective. This has fueled the pursuit of automated segmentation methods in adults. However, little is known about the reliability of these automated protocols in infants, particularly when anatomical scan quality is degraded by head motion or the use of shorter and quieter infant-friendly sequences. During a task-based fMRI protocol, we collected quiet T1-weighted anatomical scans from 42 sessions with awake infants aged 4–23 months. Two expert tracers first segmented the hippocampus in both hemispheres manually. The resulting inter-rater reliability (IRR) was only moderate, reflecting the difficulty of infant segmentation. We then used four protocols to predict these manual segmentations: average adult template, average infant template, FreeSurfer software, and Automated Segmentation of Hippocampal Subfields (ASHS) software. ASHS generated the most reliable hippocampal segmentations in infants, exceeding the manual IRR of experts. Automated methods thus provide robust hippocampal segmentations of noisy T1-weighted infant scans, opening new possibilities for interrogating early hippocampal development.     

Pain neuroscience education versus transcutaneous vagal nerve stimulation in the management of patients with fibromyalgia

Aim of the workTo evaluate the effectiveness of pain neuroscience education (PNE) and transcutaneous vagal nerve stimulation (tVNS) for fibromyalgia (FM) patients, as one of the chronic pain treatment modalities.Patients and methodsThe study was conducted on 99 patients that were divided into 3 groups (n = 33 each): Patients in group A received 6 sessions of tVNS twice weekly (25 Hz for 30 min), group B received 6 sessions of tVNS twice weekly (25 Hz for 30 min) and 3 sessions of PNE once weekly (for 30 min) and group C received 3 sessions of PNE once weekly (for 30 min). The follow up done immediately after the end of the sessions by Visual Analogue Scale score, Fibromyalgia Impact Questionnaire (FIQ), Pain catastrophizing scale questionnaire (PCS-Q, Pain DETECT questionnaire (PD-Q) and state trait anxiety inventory (STAI Q) self-reported questionnaire.ResultsThe mean age of patients was 33.3 ± 8.2 years and they were 86 females and 13 males (F:M 6.6: 1) and the 3 groups were matched for age (p = 0.15) and gender (p = 0.13). During the procedures no side effects were encountered. The 3 groups showed significant improvement of FM symptoms assessed by VAS, FIQ, PCS-Q, PD-Q and STAI-Q (state and trait), but group B showed the best results percentage of improvement (60%, 34.4%, 54.2%, 40%, 51.1% and 52,2% respectively).ConclusionCombined tVNS and PNE are more effective than PNE alone or VNS alone in management of FM. Further studies with long term follow up to assess the long-term effect of tVNS or PNE.