Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macroscale neuroanatomy and how they shape emergent function remains poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography scans in >1,200 healthy individuals to construct a whole-brain 3-D normative atlas of 18 receptors and transporters across 9 different neurotransmitter systems. We find that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncover a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we find both expected and novel associations between receptor distributions and cortical thinning patterns across 13 disorders. We replicate all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

A Precision Functional Atlas of Network Probabilities and Individual-Specific Network Topography

The brain is organized into a broad set of functional neural networks. These networks and their various characteristics have been described and scrutinized through in vivo resting state functional magnetic resonance imaging (rs-fMRI). While the basic properties of networks are generally similar between healthy individuals, there is vast variability in the precise topography across the population. These individual differences are often lost in population studies due to population averaging which assumes topographical uniformity. We leveraged precision brain mapping methods to establish a new open-source, method-flexible set of probabilistic functional network atlases: the Masonic Institute for the Developing Brain (MIDB) Precision Atlas. Using participants from the Adolescent Brain Cognitive Development (ABCD) study, single subject precision maps were generated with two supervised network-matching procedures (template matching and non-negative matrix factorization), as well as an unsupervised community detection algorithm (Infomap). We demonstrate that probabilistic network maps generated for two demographically-matched groups of n~3000 each were nearly identical, both between groups (Pearson r >0.999) and between methods (r=0.96), revealing both regions of high invariance and high variability. Compared to using parcellations based on groups averages, the MIDB Precision Atlases allowed us to derive a set of brain regions that are largely invariant in network topography and provide more reproducible statistical maps of executive function brain-wide associations. We explore an example use case for probabilistic maps, highlighting their potential for use in targeted neuromodulation. The MIDB Precision Atlas is expandable to alternative datasets and methods and is provided open-source with an online web interface to encourage the scientific community to experiment with probabilistic atlases and individual-specific topographies to more precisely relate network phenomenon to functional organization of the human brain.

Transcription shapes 3D chromatin organization by interacting with loop-extruding cohesin complexes

Cohesin organizes mammalian interphase chromosomes by reeling chromatin fibers into dynamic loops (Banigan and Mirny, 2020; Davidson et al., 2019; Kim et al., 2019; Yatskevich et al., 2019). "Loop extrusion" is obstructed when cohesin encounters a properly oriented CTCF protein (Busslinger et al., 2017; de Wit et al., 2015; Fudenberg et al., 2016; Nora et al., 2017; Sanborn et al., 2015; Wutz et al., 2017), and recent work indicates that other factors, such as the replicative helicase MCM (Dequeker et al., 2020), can also act as barriers to loop extrusion. It has been proposed that transcription relocalizes (Busslinger et al., 2017; Glynn et al., 2004; Lengronne et al., 2004) or interferes with cohesin (Heinz et al., 2018; Jeppsson et al., 2020; Valton et al., 2021; S. Zhang et al., 2021), and that active transcription start sites function as cohesin loading sites (Busslinger et al., 2017; Kagey et al., 2010; Zhu et al., 2021; Zuin et al., 2014), but how these effects, and transcription in general, shape chromatin is unknown. To determine whether transcription can modulate loop extrusion, we studied cells in which the primary extrusion barriers could be removed by CTCF depletion and cohesin's residence time and abundance on chromatin could be increased by Wapl knockout. We found evidence that transcription directly interacts with loop extrusion through a novel "moving barrier" mechanism, but not by loading cohesin at active promoters. Hi-C experiments showed intricate, cohesin-dependent genomic contact patterns near actively transcribed genes, and in CTCF-Wapl double knockout (DKO) cells (Busslinger et al., 2017), genomic contacts were enriched between sites of transcription-driven cohesin localization ("cohesin islands"). Similar patterns also emerged in polymer simulations in which transcribing RNA polymerases (RNAPs) acted as "moving barriers" by impeding, slowing, or pushing loop-extruding cohesins. The model predicts that cohesin does not load preferentially at promoters and instead accumulates at TSSs due to the barrier function of RNAPs. We tested this prediction by new ChIP-seq experiments, which revealed that the "cohesin loader" Nipbl (Ciosk et al., 2000) co-localizes with cohesin, but, unlike in previous reports (Busslinger et al., 2017; Kagey et al., 2010; Zhu et al., 2021; Zuin et al., 2014), Nipbl did not accumulate at active promoters. We propose that RNAP acts as a new type of barrier to loop extrusion that, unlike CTCF, is not stationary in its precise genomic position, but is itself dynamically translocating and relocalizes cohesin along DNA. In this way, loop extrusion could enable translocating RNAPs to maintain contacts with distal regulatory elements, allowing transcriptional activity to shape genomic functional organization.

Sensory and motor electrophysiological mapping of the cerebellum in humans

Cerebellar damage during posterior fossa surgery in children can lead to ataxia and risk of cerebellar mutism syndrome. Compartmentalisation of sensorimotor and cognitive functions within the cerebellum have been demonstrated in animal electrophysiology and human imaging studies. Electrophysiological monitoring was carried out under general anaesthesia to assess the limb sensorimotor representation within the human cerebellum for assessment of neurophysiological integrity to reduce the incidence of surgical morbidities. Thirteen adult and paediatric patients undergoing posterior fossa surgery were recruited. Sensory evoked field potentials were recorded in response to mapping (n = 8) to electrical stimulation of limb nerves or muscles. For motor mapping (n = 5), electrical stimulation was applied to the surface of the cerebellum and evoked EMG responses were sought in facial and limb muscles. Sensory evoked potentials were found in two patients (25%). Responses were located on the surface of the right inferior posterior cerebellum to stimulation of the right leg in one patient, and on the left inferior posterior lobe in another patient to stimulation of left forearm. No evoked EMG responses were found for the motor mapping. The present study identifies challenges with using neurophysiological methods to map functional organization within the human cerebellum and considers ways to improve success.

A meta-analysis of task-based differences in bilingual L1 and L2 language networks

The functional organization of first (L1) and second (L2) language processing in bilinguals remains a topic of great interest to the neurolinguistics community. Functional magnetic resonance imaging (fMRI) studies report meaningful differences in the location and extent of hemodynamic changes between tasks performed in the L1 and L2, yet there is no consensus on whether these networks can be considered truly distinct. In part, this may be due to the multiplicity of task designs implemented in such studies, which complicates the interpretation of their findings. This paper compares the results of previous bilingual meta-analyses to a new ALE meta-analysis that categorizes neuroimaging studies by task design. Factors such as the age of L2 acquisition (AoA) and the L2 language proficiency level of participants are also considered. The findings support previous accounts of the effect of participant characteristics on linguistic processing, while at the same time revealing dissociable differences in fMRI activation for L1 and L2 networks within and across tasks that appear independent of these external factors.

Transcranial stimulation of alpha oscillations up-regulates the default mode network

The default mode network (DMN) is the most-prominent intrinsic connectivity network, serving as a key architecture of the brain’s functional organization. Conversely, dysregulated DMN is characteristic of major neuropsychiatric disorders. However, the field still lacks mechanistic insights into the regulation of the DMN and effective interventions for DMN dysregulation. The current study approached this problem by manipulating neural synchrony, particularly alpha (8 to 12 Hz) oscillations, a dominant intrinsic oscillatory activity that has been increasingly associated with the DMN in both function and physiology. Using high-definition alpha-frequency transcranial alternating current stimulation (α-tACS) to stimulate the cortical source of alpha oscillations, in combination with simultaneous electroencephalography and functional MRI (EEG-fMRI), we demonstrated that α-tACS (versus Sham control) not only augmented EEG alpha oscillations but also strengthened fMRI and (source-level) alpha connectivity within the core of the DMN. Importantly, increase in alpha oscillations mediated the DMN connectivity enhancement. These findings thus identify a mechanistic link between alpha oscillations and DMN functioning. That transcranial alpha modulation can up-regulate the DMN further highlights an effective noninvasive intervention to normalize DMN functioning in various disorders.

ОСОБЛИВОСТІ БОЛЬОВОГО СИНДРОМУ У ХВОРИХ НА КРИЛОПІДНЕБІННИЙ ГАНГЛІОНІТ

Relevance of the research. The features of complex anatomical and functional organization of the maxillofacial area, peripheral nervous system, as well as autonomic structures determine a variety of pathogenetic mechanisms of prosopalgia, among which the lesions of the pterygopalatine node are the most common. Despite the presence of a significant variety of clinical manifestations of pterygopalatine ganglionitis, the prevalence and variety of autonomic manifestations in this disease, the main complaint of patients is pain, the characteristics of which are quite different. The aim of our research was to study the nature of pain in patients with pterygopalatine ganglionitis. Material and methods of research. We examined 105 patients with pterygopalatine ganglionitis aged from 30 to 74 years. Patients were examined for the nature of pain and its intensity, the predominant time of onset and duration of pain attacks, the place of primary localization of pain and the area of its spread. A visual analog scale (VAS) was used to assess pain intensity. Based on the intensity of pain and depending on the severity of the disease, all patients were divided into three groups: mild, moderate and severe pterygopalatine ganglionitis. With a mild severity of pterygopalatine ganglionitis, the intensity of pain attacks is 4-5 points, lasting up to 30 minutes and with a frequency of 1-3 times a day with localization within one or two anatomical areas. With moderate severity, the intensity of pain attacks is 5-7 points, lasting from 30 minutes to 1-2 hours and with a frequency of 4-5 times a day with the gradual spread of pain from one area to half of the face. The severe course is characterized by pain attacks of 8-10 points, lasting for 2 hours or more and with a frequency of attacks from 4 to 6-10 per day. In addition, the pain, occurring in one anatomical area, gradually spread to half of the face, radiating to neighboring areas. Thus, analyzing the features of the pain syndrome in patients with pterygopalatine ganglionitis, we can conclude: 1. The intensity of pain, which was determined by VAS, increases depending on the severity of ganglionitis and ranges from 4.3 points in mild to 8.75 in severe ganglionitis. 2. The duration and frequency of pain attacks increase from 30 minutes with a frequency of 1-3 seizures per day in patients with mild pterygopalatine ganglionitis, to 2 or more hours and 4-10 seizures per day in patients with severe ganglionitis. 3. The localization of pain attacks extends from one anatomical area in mild ganglionitis to half of the face with the possibility of irradiation of pain in severe ganglionitis. 4. These clinical symptoms should be used in determining the severity of pterygopalatine ganglionitis and the choice of treatment tactics in the future.

Microperimetry in Children’s Practice

Child health is a global health priority. The program “Elimination of Eliminable Blindness in the World of Vision-2020” gives the fourth place to the problems of pediatric ophthalmopathology and creates targeted programs for their elimination. The introduction of modern equipment in the clinical practice of pediatric ophthalmologists has expanded the boundaries of traditional diagnostics. Microperimetry is an innovative, quantitative, non-invasive diagnostic study aimed at assessing the functional ability of the retina in strict correlation with morphology. Along with the assessment of light sensitivity, the device allows you to measure fixation parameters, which serves as a reliable criterion for its stability and indirectly reflects the functional organization of central vision. In this regard, the literature review presents the results of domestic and foreign researchers who used microperimetric testing as the main or additional research method for diseases of various etiologies, such as hereditary retinal diseases, amblyopia, and nystagmus. Most authors have demonstrated the high diagnostic significance of this method, the ability to assess photosensitivity of the retina, the detection of fixation disorders, such as eccentricity and instability, even in pediatric patients. The use of microperimetry as a new method of treatment for these diseases has also been shown. Visual rehabilitation based on biofeedback provided by this device has shown high efficiency in diseases of the central region. More research remains to be done to determine future potential applications of this technology, in particular in pediatric practice, and to develop the potential of microperimetry as a tool for the visual rehabilitation of patients.

Scaffolding layered control architectures through constraint closure: insights into brain evolution and development

The functional organization of the mammalian brain can be considered to form a layered control architecture, but how this complex system has emerged through evolution and is constructed during development remains a puzzle. Here we consider brain organization through the framework of constraint closure, viewed as a general characteristic of living systems, that they are composed of multiple sub-systems that constrain each other at different timescales. We do so by developing a new formalism for constraint closure, inspired by a previous model showing how within-lifetime dynamics can constrain between-lifetime dynamics, and we demonstrate how this interaction can be generalized to multi-layered systems. Through this model, we consider brain organization in the context of two major examples of constraint closure—physiological regulation and visual orienting. Our analysis draws attention to the capacity of layered brain architectures to scaffold themselves across multiple timescales, including the ability of cortical processes to constrain the evolution of sub-cortical processes, and of the latter to constrain the space in which cortical systems self-organize and refine themselves. This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.

Anatomic variability of the nerves of the triceps surae in early human fetuses

Background. Establishing fetal anatomical variability of intramuscular nerves and their connections plays an important role in the search for and development of new methods for the diagnostic and treatment posterior region of the leg. Objective – to find out the topographic and anatomical features of the innervation of the triceps surae in human fetuses 4-6 months. Methods. The study was performed on 46 human fetuses 81.0-230.0 mm crown-rump length (CRL) length using macromicroscopic preparation, vascular injection, and morphometry. Results. In early human fetuses, the anatomical variability of the distribution of intramuscular nerves in the thickness of the triceps surae was established, which is due to the variability of the structure and topography of the tibial nerve, structural and functional organization of triceps surae, arterial branching and interneural connections in the thickness of the heads of the gastrocnemius and soleus in fetuses of different and the same age groups, and sometimes in the same fetus. Conclusion. The main source of innervation of the triceps surae is the tibial nerve, which can be presented by a single trunk, main and additional trunks, or several independent trunks. The nerves in the thickness of the triceps are unevenly distributed. The highest concentration of muscular branches of the tibial nerve is determined in the medial head of the gastrocnemius and the medial part of the soleus. Information on fetal topography of intramuscular nerves in the thickness of the right and left triceps surae, as well as forms of their anatomical variability, both in fetuses of different and the same age and sometimes in the same fetus, due to structural-functional organization of the components of the triceps surae, the type of branching of arteries and nerves in the thickness of the heads of the gastrocnemius and soleus. Atypical variants of the topography of the tibial nerve and common fibular nerve in early fetuses, as well as interneural connections in the thickness of the components of the triceps surae, are more common on the right lower leg.