Conditions for multi-functionality in a rhythm generating network inspired by turtle scratching

Rhythmic behaviors such as breathing, walking, and scratching are vital to many species. Such behaviors can emerge from groups of neurons, called central pattern generators, in the absence of rhythmic inputs. In vertebrates, the identification of the cells that constitute the central pattern generator for particular rhythmic behaviors is difficult, and often, its existence has only been inferred. For example, under experimental conditions, intact turtles generate several rhythmic scratch motor patterns corresponding to non-rhythmic stimulation of different body regions. These patterns feature alternating phases of motoneuron activation that occur repeatedly, with different patterns distinguished by the relative timing and duration of activity of hip extensor, hip flexor, and knee extensor motoneurons. While the central pattern generator network responsible for these outputs has not been located, there is hope to use motoneuron recordings to deduce its properties. To this end, this work presents a model of a previously proposed central pattern generator network and analyzes its capability to produce two distinct scratch rhythms from a single neuron pool, selected by different combinations of tonic drive parameters but with fixed strengths of connections within the network. We show through simulation that the proposed network can achieve the desired multi-functionality, even though it relies on hip unit generators to recruit appropriately timed knee extensor motoneuron activity, including a delay relative to hip activation in rostral scratch. Furthermore, we develop a phase space representation, focusing on the inputs to and the intrinsic slow variable of the knee extensor motoneuron, which we use to derive sufficient conditions for the network to realize each rhythm and which illustrates the role of a saddle-node bifurcation in achieving the knee extensor delay. This framework is harnessed to consider bistability and to make predictions about the responses of the scratch rhythms to input changes for future experimental testing

Correlation transfer from basal ganglia to thalamus in Parkinson’s disease

There is much experimental evidence that neurons located in the basal ganglia of parkinsonian primates show increased pairwise correlations, oscillatory activity, and burst rate compared to normal brain activity. Past computational work has suggested that such changes in the firing pattern of neurons in the globus pallidus internus (GPi), the main output nucleus of the basal ganglia, may compromise thalamocortical relay capabilities. To understand how changes in the patterns of basal ganglia activity affect correlation transfer, we study pairs of realistic models of thalamocortical (TC) relay neurons receiving correlated inhibitory input from the GPi, as well as uncorrelated excitatory signals from cortex. We observe that bursty firing patterns such as those seen in the parkinsonian GPi allow for stronger transfer of correlations and higher correlation susceptibility than do firing patterns found under normal conditions. We also show that removing the T-current in the TC neurons does not significantly affect the correlation transfer, despite its pronounced effects on the spiking of the neurons. Oscillatory firing patterns in GPi are shown to affect the time scale at which correlations are best transferred through the system. We obtain the same results using an integrate-and-fire-or-burst (IFB) model of TC neurons as we do with a more realistic conductance-based model of the TC neurons, suggesting that the IFB model is a good reduced model for studying correlation transfer. In a reduced point process model, we derive analytic calculations of the spike count correlation coefficient for the time-inhomogeneous case. The analysis indicates that the rhythms seen in the transfer of correlations at varying time scales are very robust to different levels of spike correlations and rate correlations between the neurons. It also points to the fact that these rhythms can be seen because of differences in instantaneous spike correlations, even when the long time scale rhythmic modulation of the neurons in identical. Overall, these results show that parkinsonian firing patterns in GPi do indeed affect the way that correlations are transferred to the thalamus

Neuronal bursting: interactions of the persistent sodium and CAN currents

The pre-Botzinger complex (pBC) is a heterogeneous neuronal network within the mammalian brainstem and has been experimentally found to generate robust, synchronous bursts [1]. Significant modeling research has been conducted on characterizing the dynamics of individual neurons within the pBC. [2, 3] It is well known that the persistent sodium current (INaP) contributes to square-wave bursting seen in the pBC [4]. Recent experimental work within the pBC identified a signaling cascade that starts with presynaptic glutamate and ends with the release of intracellular calcium that activates a nonspecific cationic current (ICAN) [5]. A subsequent model demonstrated that ICAN may contribute to bursts within the pBC that exhibit depolarization block [6]. With these two mechanisms for generating bursts present within the pBC, an open question is how do they combine to generate the robust bursts seen in the network? The present work seeks to analyze the result of including both INaP and ICAN within the same model. We consider the effects of heterogeneity in the conductance gNaP of INaP and the conductance gCAN of ICAN; with this heterogeneity in mind, the model cell may be quiescent, tonically active, have only square-wave bursts, have only depolarization-block exhibiting bursts, or may show both types of bursting. Using the mathematical tools of bifurcation analysis and slow-fast decomposition, we illuminate the mechanisms underlying the transitions of a model cell between the types of dynamics listed above. Our results show that, in cases where gCAN is relatively high, increasing gNaP increases the range of gCAN where the resultant cell has depolarization-block exhibiting bursts. On the other hand, when gCAN is relatively low, increasing gNaP may cause the cell to transition from quiescence, to square wave bursting, to tonic activity, to square wave bursts with high duty cycles, and finally further increase of gNaP causes the cell to again be tonically active. The latter two transitions do not occur if ICAN is absent. The interactions of ICAN and INaP are relevant to many systems beyond the pBC. Individually, ICAN and INaP have been focused on as important to rhythmic burst generation in other systems such as the entorhinal cortex [7]; however, it is likely that both currents are present in these systems. Thus, a detailed account for the interaction of ICAN and INaP may help explain the rhythm generation encountered in other systems beyond the pBC

A closed-loop model of the respiratory system: Focus on hypercapnia and active expiration

Breathing is a vital process providing the exchange of gases between the lungs and atmosphere. During quiet breathing, pumping air from the lungs is mostly performed by contraction of the diaphragm during inspiration, and muscle contraction during expiration does not play a significant role in ventilation. In contrast, during intense exercise or severe hypercapnia forced or active expiration occurs in which the abdominal "expiratory" muscles become actively involved in breathing. The mechanisms of this transition remain unknown. To study these mechanisms, we developed a computational model of the closed-loop respiratory system that describes the brainstem respiratory network controlling the pulmonary subsystem representing lung biomechanics and gas (O2and CO2) exchange and transport. The lung subsystem provides two types of feedback to the neural subsystem: a mechanical one from pulmonary stretch receptors and a chemical one from central chemoreceptors. The neural component of the model simulates the respiratory network that includes several interacting respiratory neuron types within the Bötzinger and pre-Bötzinger complexes, as well as the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) representing the central chemoreception module targeted by chemical feedback. The RTN/pFRG compartment contains an independent neural generator that is activated at an increased CO2level and controls the abdominal motor output. The lung volume is controlled by two pumps, a major one driven by the diaphragm and an additional one activated by abdominal muscles and involved in active expiration. The model represents the first attempt to model the transition from quiet breathing to breathing with active expiration. The model suggests that the closed-loop respiratory control system switches to active expiration via a quantal acceleration of expiratory activity, when increases in breathing rate and phrenic amplitude no longer provide sufficient ventilation. The model can be used for simulation of closed-loop control of breathing under different conditions including respiratory disorders

Prevalence of type 2 diabetes in psychiatric disorders: an umbrella review with meta-analysis of 245 observational studies from 32 systematic reviews

Aims/hypothesis: Estimates of the global prevalence of type 2 diabetes vary between 6% and 9%. The prevalence of type 2 diabetes has been investigated in psychiatric populations but a critical appraisal of the existing evidence is lacking, and an overview is needed. This umbrella review summarises existing systematic reviews of observational studies investigating the prevalence of type 2 diabetes in people with a psychiatric disorder. / Methods: We searched PubMed, EMBASE, PsycINFO and the Cochrane Database of Systematic Reviews from inception to 17 January 2021 and screened reference lists of included systematic reviews. On the basis of prespecified criteria, we included systematic reviews investigating the prevalence of type 2 diabetes in adults (aged ≥18 years) with a psychiatric disorder. Titles and abstracts of 5155 identified records and full texts of 431 selected studies were screened by two independent reviewers, based on predefined eligibility criteria and an a priori developed extraction form, following the PRISMA and MOOSE guidelines. Risk of bias was assessed with the ROBIS instrument. Data extracted from primary studies were synthesised using random-effects meta-analyses. / Results: A total of 32 systematic reviews with 245 unique primary studies were identified and met inclusion criteria. Twelve had low risk of bias. They reported type 2 diabetes prevalence estimates ranging from 5% to 22% depending on the specific psychiatric disorder. We meta-analysed data for ten categories of psychiatric disorders and found the following prevalence estimates of type 2 diabetes: in people with a sleep disorder: 40%; binge eating disorder: 21%; substance use disorder: 16%; anxiety disorder: 14%; bipolar disorder: 11%; psychosis: 11%; schizophrenia: 10%; a mixed group of psychiatric disorders: 10%; depression: 9%; and in people with an intellectual disability 8%. All meta-analyses revealed high levels of heterogeneity. / Conclusions/interpretation: Type 2 diabetes is a common comorbidity in people with a psychiatric disorder. Future research should investigate whether routine screening for type 2 diabetes and subsequent prevention initiatives for these people are warranted

Why is there no queer international theory?

Over the last decade, Queer Studies have become Global Queer Studies, generating significant insights into key international political processes. Yet, the transformation from Queer to Global Queer has left the discipline of International Relations largely unaffected, which begs the question: if Queer Studies has gone global, why has the discipline of International Relations not gone somewhat queer? Or, to put it in Martin Wight’s provocative terms, why is there no Queer International Theory? This article claims that the presumed non-existence of Queer International Theory is an effect of how the discipline of International Relations combines homologization, figuration, and gentrification to code various types of theory as failures in order to manage the conduct of international theorizing in all its forms. This means there are generalizable lessons to be drawn from how the discipline categorizes Queer International Theory out of existence to bring a specific understanding of International Relations into existence

Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study.

ObjectiveTo assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).MethodsPatients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.ResultsAt week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation.ConclusionsElosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile