Resting EEG Microstates and Autonomic Heart Rate Variability Do Not Return to Baseline One Hour After a Submaximal Exercise.

Recent findings suggest that an acute physical exercise modulates the temporal features of the EEG resting microstates, especially the microstate map C duration and relative time coverage. Microstate map C has been associated with the salience resting state network, which is mainly structured around the insula and cingulate, two brain nodes that mediate cardiovascular arousal and interoceptive awareness. Heart rate variability (HRV) is dependent on the autonomic balance; specifically, an increase in the sympathetic (or decrease in the parasympathetic) tone will decrease variability while a decrease in the sympathetic (or increase in the parasympathetic) tone will increase variability. Relying on the functional interaction between the autonomic cardiovascular activity and the salience network, this study aims to investigate the effect of exercise on the resting microstate and the possible interplay with this autonomic cardiovascular recovery after a single bout of endurance exercise. Thirty-eight young adults performed a 25-min constant-load cycling exercise at an intensity that was subjectively perceived as "hard." The microstate temporal features and conventional time and frequency domain HRV parameters were obtained at rest for 5 min before exercise and at 5, 15, 30, 45, and 60 min after exercise. Compared to the baseline, all HRV parameters were changed 5 min after exercise cessation. The mean durations of microstate B and C, and the frequency of occurrence of microstate D were also changed immediately after exercise. A long-lasting effect was found for almost all HRV parameters and for the duration of microstate C during the hour following exercise, indicating an uncompleted recovery of the autonomic cardiovascular system and the resting microstate. The implication of an exercise-induced afferent neural traffic is discussed as a potential modulator of both the autonomic regulation of heart rate and the resting EEG microstate

Movement-Related Cortical Potential Amplitude Reduction after Cycling Exercise Relates to the Extent of Neuromuscular Fatigue.

Exercise-induced fatigue affects the motor control and the ability to generate a given force or power. Surface electroencephalography allows researchers to investigate movement-related cortical potentials (MRCP), which reflect preparatory brain activity 1.5 s before movement onset. Although the MRCP amplitude appears to increase after repetitive single-joint contractions, the effects of large-muscle group dynamic exercise on such pre-motor potential remain to be described. Sixteen volunteers exercised 30 min at 60% of the maximal aerobic power on a cycle ergometer, followed by a 10-km all-out time trial. Before and after each of these tasks, knee extensor neuromuscular function was investigated using maximal voluntary contractions (MVC) combined with electrical stimulations of the femoral nerve. MRCP was recorded during 60 knee extensions after each neuromuscular sequence. The exercise resulted in a significant decrease in the knee extensor MVC force after the 30-min exercise (-10 ± 8%) and the time trial (-21 ± 9%). The voluntary activation level (VAL; -6 ± 8 and -12 ± 10%), peak twitch (Pt; -21 ± 16 and -32 ± 17%), and paired stimuli (P100 Hz; -7 ± 11 and -12 ± 13%) were also significantly reduced after the 30-min exercise and the time trial. The first exercise was followed by a decrease in the MRCP, mainly above the mean activity measured at electrodes FC1-FC2, whereas the reduction observed after the time trial was related to the FC1-FC2 and C2 electrodes. After both exercises, the reduction in the late MRCP component above FC1-FC2 was significantly correlated with the reduction in P100 Hz (r = 0.61), and the reduction in the same component above C2 was significantly correlated with the reduction in VAL (r = 0.64). In conclusion, large-muscle group exercise induced a reduction in pre-motor potential, which was related to muscle alterations and resulted in the inability to produce a maximal voluntary contraction

Dopamine Transporter Deficiency Syndrome (DTDS): Expanding the Clinical Phenotype and Precision Medicine Approaches

Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the SLC6A3 gene. Advances in genomic analysis have revealed an evolving spectrum of SLC6A3-related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy

Gene Therapy for Dopamine Dyshomeostasis: From Parkinson's to Primary Neurotransmitter Diseases

Neurological disorders encompass a broad range of neurodegenerative and neurodevelopmental diseases that are complex and almost universally without disease modifying treatments. There is, therefore, significant unmet clinical need to develop novel therapeutic strategies for these patients. Viral gene therapies are a promising approach, where gene delivery is achieved through viral vectors such as adeno-associated virus and lentivirus. The clinical efficacy of such gene therapies has already been observed in two neurological disorders of pediatric onset; for spinal muscular atrophy and aromatic L-amino acid decarboxylase (AADC) deficiency, gene therapy has significantly modified the natural history of disease in these life-limiting neurological disorders. Here, we review recent advances in gene therapy, focused on the targeted delivery of dopaminergic genes for Parkinson's disease and the primary neurotransmitter disorders, AADC deficiency and dopamine transporter deficiency syndrome (DTDS). Although recent European Medicines Agency and Medicines and Healthcare products Regulatory Agency approval of Upstaza (eladocagene exuparvovec) signifies an important landmark, numerous challenges remain. Future research will need to focus on defining the optimal therapeutic window for clinical intervention, better understanding of the duration of therapeutic efficacy, and improved brain targeting. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Regulation of CD1 Antigen-presenting Complex Stability

For major histocompatibility complex class I and II molecules, the binding of specific peptide antigens is essential for assembly and trafficking and is at the center of their quality control mechanism. However, the role of lipid antigen binding in stabilization and quality control of CD1 heavy chain (HC).beta(2)-microglobulin (beta(2)m) complexes is unclear. Furthermore, the distinct trafficking and loading routes of CD1 proteins take them from mildly acidic pH in early endososmal compartments (pH 6.0) to markedly acidic pH in lysosomes (pH 5.0) and back to neutral pH of the cell surface (pH 7.4). Here, we present evidence that the stability of each CD1 HC.beta(2)m complex is determined by the distinct pH optima identical to that of the intracellular compartments in which each CD1 isoform resides. Although stable at acidic endosomal pH, complexes are only stable at cell surface pH 7.4 when bound to specific lipid antigens. The proposed model outlines a quality control program that allows lipid exchange at low endosomal pH without dissociation of the CD1 HC.beta(2)m complex and then stabilizes the antigen-loaded complex at neutral pH at the cell surface

Ancestry patterns inferred from massive RNA-seq data

There is a growing body of evidence suggesting that patterns of gene expression vary within and between human populations. However, the impact of this variation in human diseases has been poorly explored, in part owing to the lack of a standardized protocol to estimate biogeographical ancestry from gene expression studies. Here we examine several studies that provide new solid evidence indicating that the ancestral background of individuals impacts gene expression patterns. Next, we test a procedure to infer genetic ancestry from RNA-seq data in 25 data sets where information on ethnicity was reported. Genome data of reference continental populations retrieved from The 1000 Genomes Project were used for comparisons. Remarkably, only eight out of 25 data sets passed FastQC default filters. We demonstrate that, for these eight population sets, the ancestral background of donors could be inferred very efficiently, even in data sets including samples with complex patterns of admixture (e.g., American-admixed populations). For most of the gene expression data sets of suboptimal quality, ancestral inference yielded odd patterns. The present study thus brings a cautionary note for gene expression studies highlighting the importance to control for the potential confounding effect of ancestral genetic background

Educational Level Is Related to Physical Fitness in Patients with Type 2 Diabetes - A Cross-Sectional Study.

Low educational level (EL) and low physical fitness are both predictors of increased morbidity and mortality in patients with type 2 diabetes. It is unknown if EL is related to physical fitness. This would have important implication for the treatment approach of patients of low EL. In 2011/12, we invited participants of a new nationwide Swiss physical activity program for patients with type 2 diabetes to participate in this study. EL was defined by self-report and categorized as low (mandatory education), middle (professional education) or high (high school/university). Physical fitness was determined using 5 validated measures that assessed aerobic fitness, functional lower limb muscle strength, walking speed, balance and flexibility. Potential confounder variables such as other socio-cultural factors, physical activity level, body composition, diabetes-related parameters and complications/co-morbidities as well as well-being were assessed. All invited 185 participants (mean age 59.6 ±9.8 yrs, 76 women) agreed to be included. Of all patients, 23.1% had a low, 32.7% a middle and 44.2% a high EL; 41.8% were professionally active. The study population had a mean BMI of 32.4±5.2 kg/m2 and an HbA1c of 7.3±1.3%. The mean diabetes duration was 8.8±7.4 years. In the baseline assessment, higher EL was associated with increased aerobic fitness, increased functional lower limb muscle strength, and increased walking speed using linear regression analysis (values for low, middle and high EL, respectively: 91.8 ± 27.9, 116.4 ± 49.7 and 134.9 ± 60.4 watts for aerobic fitness (p = 0.002), 15 ± 4.7, 13.9 ± 2.7, 12.6 ± 2.9 seconds for strength (p = 0.001) and 8.8 ± 1.6, 8.3 ± 1.4, 7.8 ± 1.4 seconds for walking speed (p = 0.004)). These associations were independent of potential confounders. Overall, aerobic fitness was 46%, functional limb muscle strength 16%, and walking speed 11% higher in patients of high compared to those of low EL. EL was not related to balance or flexibility. A main strength of the present study is that it addresses a population of importance and a factor (EL) whose understanding can influence future interventions. A second strength is its relatively large sample size of a high-risk population. Third, unlike studies that have shown an association between self-reported fitness and educational level we assessed physical fitness measures by a quantitative and validated test battery using assessors blinded to other data. Another novelty is the extensive evaluation of the role of many relevant confounder variables. In conclusion, we show that in patients with type 2 diabetes EL correlates favorably and independently with important health-related physical fitness measures such as aerobic fitness, walking speed, and lower limb strength. Our findings underline that diabetic patients with low EL should be specifically encouraged to participate in physical activity intervention programs to further reduce social disparities in healthcare. Such programs should be structured and integrate the norms, needs and capacities (financial, time, physical capacities and self-efficacy) of this population, and their effectiveness should be tested in future studies. University of Lausanne clinicaltrials.gov NCT01289587

Generic Multifractality in Exponentials of Long Memory Processes

We find that multifractal scaling is a robust property of a large class of continuous stochastic processes, constructed as exponentials of long-memory processes. The long memory is characterized by a power law kernel with tail exponent $\phi+1/2$, where $\phi >0$. This generalizes previous studies performed only with $\phi=0$ (with a truncation at an integral scale), by showing that multifractality holds over a remarkably large range of dimensionless scales for $\phi>0$. The intermittency multifractal coefficient can be tuned continuously as a function of the deviation $\phi$ from 1/2 and of another parameter $\sigma^2$ embodying information on the short-range amplitude of the memory kernel, the ultra-violet cut-off (``viscous'') scale and the variance of the white-noise innovations. In these processes, both a viscous scale and an integral scale naturally appear, bracketing the ``inertial'' scaling regime. We exhibit a surprisingly good collapse of the multifractal spectra $\zeta(q)$ on a universal scaling function, which enables us to derive high-order multifractal exponents from the small-order values and also obtain a given multifractal spectrum $\zeta(q)$ by different combinations of $\phi$ and $\sigma^2$.Comment: 10 pages + 9 figure