Electrophysiological Differences Research Articles

Neural evidence of core foundations and conceptual change in preschool numeracy.

Symbolic numeracy first emerges as children learn the meanings of number words and how to use them to precisely count sets of objects. This development starts before children enter school and forms a foundation for lifelong mathematics achievement. Despite its importance, exactly how children acquire this basic knowledge is unclear. Here we test competing theories of early number learning by measuring event-related brain potentials during a novel number word-quantity comparison task in 3-4-year-old preschool children (N=128). We find several qualitative differences in neural processing of number by conceptual stage of development. Specifically, we find differences in early attention-related parietal electrophysiology (N1), suggesting that less conceptually advanced children process arrays as individual objects and more advanced children distribute attention over the entire set. Subsequently, we find that only more conceptually advanced children show later-going frontal (N2) sensitivity to the numerical-distance relationship between the number word and visual quantity. The nature of this response suggested thatexact rather than approximate numerical meanings were being associated with number words over frontal sites. No evidence of numerical distance effects was observed over posterior scalp sites. Together these results suggest that children may engage parallel individuation of objects to learn the meanings of the first few number words, but, ultimately, create new exact cardinal value representations for number words that cannot be defined in terms of core, nonverbal number systems. More broadly, these results document an interaction between attentional and general cognitive mechanisms in cognitive development. RESEARCH HIGHLIGHTS: Conceptual development in numeracy is associated with a shift in attention from objects to sets. Children acquire meanings of the first few number words through associations with parallel attentional individuation of objects. Understanding of cardinality is associated with attentional processing of sets rather than individuals. Brain signatures suggest children attribute exact rather than approximate numerical meanings to the first few number words. Number-quantity relationship processing for the first few number words is evident in frontal but not parietal scalp electrophysiology of young children.

Electrophysiological differences of randomized deep sedation with dexmedetomidine versus propofol

BackgroundDexmedetomidine and propofol are common sedatives in intensive care units and for interventional procedures. Both may compromise sinus node function and atrioventricular conduction.The objective of this prospective, randomized study is to compare the effect of dexmedetomidine with propofol on sinus node function and atrioventricular conduction.MethodsIn a tertiary care center in Switzerland we included from September 2019 to October 2020 160 patients (65 ± 11 years old; 32% female) undergoing first ablation for atrial fibrillation by cryoballoon ablation or by radiofrequency ablation.Patients were randomly assigned to deep sedation with dexmedetomidine (DEX group) versus propofol (PRO group). A standard electrophysiological study was performed after pulmonary vein isolation with the patients still deeply sedated and hemodynamically stable.ResultsEighty patients each were randomized to the DEX and PRO group. DEX group patients had higher baseline sinus cycle length (1022 vs. 1138 ms; p = 0.003) and longer sinus node recovery time (SNRT400; 1597 vs. 1412 ms; p = 0.042). However, both corrected SNRT and normalized SNRT did not differ. DEX group patients had longer PR interval (207 vs. 186 ms; p = 0.002) and AH interval (111 vs. 95 ms, p = 0.008), longer Wenckebach cycle length of the atrioventricular node (512 vs. 456 ms; p = 0.005), and longer atrioventricular node effective refractory period (390 vs. 344 ms; p = 0.009). QRS width and HV interval were not different. An arrhythmia, mainly atrial fibrillation, was induced in 33 patients during the electrophysiological study, without differences among groups (20% vs. 15%, p = 0.533).ConclusionsDexmedetomidine has a more pronounced slowing effect on sinus rate and suprahissian AV conduction than propofol, but not on infrahissian AV conduction and ventricular repolarization. These differences need to be taken into account when using these sedatives.Trial registrationClinicalTrials.gov number NCT03844841, 19/02/2019

Biophysical phenotyping of single-cell based on impedance and application for individualized precision medicine

Single-cell biophysical characterization based on impedance measurement is an advantageous approach due to its label-free, high-efficiency, cost-effective and real-time capability. Biophysical phenotyping can yield timely and rich information on physiological and pathological state of cells for disease diagnosis, drug screening, precision medicine, etc. However, precise measurement on single-cell impedance is challenging, particularly hard to figure out the detailed biophysical parameters of single cell due to coupling and complexity of impedance model. Here, we propose an analytic determination method to decode single-cell electrophysiological parameters (including cell-substrate interface capacitance, cell membrane capacitance, cell membrane conductivity, and cytoplasm conductivity) from the impedances measured at optimized frequencies by using analytic solution rather than spectrum fitting. With this simple and fast analytic solution method, the physiological parameters of single cell in natural adhesion state can be accurately determined in real time. We validate this cell parameter determination method in monitoring the change of cell adhesion under hydraulic effects and exploring electrophysiological differences among MCF-7, HeLa, Huh7, and MDA-MB-231 cell lines. Particularly, we apply the approach to optimize tumor treating fields (TTFields) therapy, realizing individualized precision medicine. Our work provides an accurate and efficient approach for characterizing single-cell biophysical properties with real-time, in-situ, label-free, and less invasive advantages.

Upregulated ECM genes and increased synaptic activity in Parkinson’s human DA neurons with PINK1/ PRKN mutations

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. Primary symptoms of PD arise with the loss of dopaminergic (DA) neurons in the Substantia Nigra Pars Compacta, but PD also affects the hippocampus and cortex, usually in its later stage. Approximately 15% of PD cases are familial with a genetic mutation. Two of the most associated genes with autosomal recessive (AR) early-onset familial PD are PINK1 and PRKN. In vitro studies of these genetic mutations are needed to understand the neurophysiological changes in patients’ neurons that may contribute to neurodegeneration. In this work, we generated and differentiated DA and hippocampal neurons from human induced pluripotent stem cells (hiPSCs) derived from two patients with a double mutation in their PINK1 and PRKN (one homozygous and one heterozygous) genes and assessed their neurophysiology compared to two healthy controls. We showed that the synaptic activity of PD neurons generated from patients with the PINK1 and PRKN mutations is impaired in the hippocampus and dopaminergic neurons. Mutant dopaminergic neurons had enhanced excitatory post-synaptic activity. In addition, DA neurons with the homozygous mutation of PINK1 exhibited more pronounced electrophysiological differences compared to the control neurons. Signaling network analysis of RNA sequencing results revealed that Focal adhesion and ECM receptor pathway were the top two upregulated pathways in the mutant PD neurons. Our findings reveal that the phenotypes linked to PINK1 and PRKN mutations differ from those from other PD mutations, suggesting a unique interplay between these two mutations that drives different PD mechanisms.

Electrophysiological and behavioral differences of general and food-specific inhibitory control in people with different levels of intuitive eating

Intuitive eating influences health-related behaviors (including calorie and nutritional intake) that are modulated by inhibitory control, producing implications for physical, mental, and emotional health. However, little is known about the relationship between intuitive eating habits and inhibitory control. Therefore, we tested intuitive eating's influence on measures of general and food-related inhibitory control using behavioral and event-related potentials (N2 and P3 components). We included 40 healthy participants: 23 had a higher level of intuitive eating, and 17 had a lower level. They participated in food-specific go/no-go and general go/no-go tasks for which we recorded electroencephalogram data. As expected, in the food-specific go/no-go task, the P3 component amplitude in the lower intuitive eating group was significantly larger than in the higher intuitive eating group; there were no significant between-group differences in the N2 amplitudes or behavioral measures. Moreover, there were no ERP or behavioral difference between groups in the general go/no-go task. Further research is needed to understand the role of positive eating behaviors in food-specific inhibitory control.

Molecular, Morphological and Electrophysiological Differences between Alpha and Gamma Motoneurons with Special Reference to the Trigeminal Motor Nucleus of Rat.

The muscle contraction during voluntary movement is controlled by activities of alpha- and gamma-motoneurons (αMNs and γMNs, respectively). In spite of the recent advances in research on molecular markers that can distinguish between αMNs and γMNs, electrophysiological membrane properties and firing patterns of γMNs have remained unknown, while those of αMNs have been clarified in detail. Because of the larger size of αMNs compared to γMNs, blindly or even visually recorded MNs were mostly αMNs, as demonstrated with molecular markers recently. Subsequently, the research on αMNs has made great progress in classifying their subtypes based on the molecular markers and electrophysiological membrane properties, whereas only a few studies demonstrated the electrophysiological membrane properties of γMNs. In this review article, we provide an overview of the recent advances in research on the classification of αMNs and γMNs based on molecular markers and electrophysiological membrane properties, and discuss their functional implication and significance in motor control.

A Morphologically Distinct Subclass of Somatostatin-expressing Interneurons in the Somatosensory Cortex are Strongly Recruited by Input from the Motor Cortex

The motor cortex (M1) and somatosensory cortex (S1) are strongly interconnected regions, and their interactions are essential for sensory perception and motor execution. However, the mechanisms by which M1 activity modulates sensory processing within S1 are poorly understood. In particular, M1 recruitment of distinct GABAergic inhibitory cells could impact S1 responsiveness. Preliminary work in our lab identified a subpopulation of somatostatin (SOM) expressing inhibitory interneurons in layer 6 (L6) of S1 that are strongly recruited by M1 input. We hypothesize these M1-responding L6 SOM cells are an electrophysiological and morphologically distinct subclass that express the enzyme neuronal nitric oxide synthase (nNOS). To stimulate the M1 to S1 pathway and test this hypothesis, we injected adeno-associated virus (AAV) encoding the light-sensitive cation channel, channelrhodopsin-2 (ChR2), in M1 of postnatal day 21 (+/-1) mice in vivo. After three weeks of expression, we prepared acute coronal brain slices for targeted loose-patch recordings and selective optical stimulation of M1 terminals. We found two groups of L6 SOM cells based on their spiking behavior during photostimulation: responsive (15%) and non-responsive (85%). Whole-cell recordings and neurobiotin injections into responsive and non-responsive SOM cells revealed robust electrophysiological and morphological differences. Initial anatomical reconstructions indicate that the non-responsive SOM cells (n=12) exhibit both Martinotti (with an L1 axonal projection) and non-Martinotti (no L1 axonal projection) morphologies, whereas the responsive SOM cells had axonal arborizations projecting toward the underlying white matter (n=10). The responsive SOM cells had quasi-fast-spiking electrophysiological properties (n=10) and were negative for nNOS (n=9), whereas the non-responsive SOM cells exhibited non-adaptive spiking behavior. Importantly, responsive SOM cells were negative for parvalbumin (PV), a marker for a distinct class of fast-spiking interneurons in the cortex, indicating these cells were not mislabeled PV cells due to the known off-target recombination in the SOM-IRES-Cre mouse line (n=4). In summary, our data show that input from M1 strongly recruits a previously unknown SOM-expressing interneuron in lower L6 with distinct morphological and electrophysiological features that could influence sensory responsiveness in S1. Future studies will focus on the mechanisms of this selective activation and identifying the postsynaptic targets of these cells to further our understanding of this sensorimotor circuit. NIH R01NS117636 (SRC); APS SURF (MKS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Error processing in young adulthood: Age-related differences in electrophysiology and behavioral performance.

The error-related negativity (ERN) and the error positivity (Pe) are electrophysiological components of error processing that develop throughout adolescence and into adulthood. As young people in their early 20s make many important life decisions, the inability to monitor and adapt behavior appropriately may interfere with their personal goals, such as educational or professional achievements. The aim of this study was to investigate age-related differences in error processing across young adulthood. Using electroencephalography and the go/no-go task, we examined behavioral (error rates, reaction times, posterror slowing [PES]) and event-related potential (ERN, Pe) indexes of error processing. Ninety-five participants were divided into three age groups: Early 20s (ages 19-21), Mid 20s (ages 23-26), and Early 30s (ages 28-44). At the beginning of the 20s, young adults still make impetuous errors and do not show PES afterward, contrary to young adults in their early 30s. Larger ERN and smaller Pe amplitude in Early 30s suggest that adult-like error processing results in early enhancement of effortful stimulus control mechanism (ERN) and the reduction in later response evaluation process (Pe). Our findings suggest that the response strategies, both behavioral and neurocognitive, which would assure stable performance resembling adult levels, may still not be reached in the early 20s. Well-timed interventions could help reduce the impact of these tendencies by introducing strategies that provide more efficient performance. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

IPSC-cardiomyocytes in the preclinical prediction of candidate pharmaceutical toxicity.

Many challenges remain in the preclinical evaluation, adjudication, and prioritization of novel compounds in therapeutic discovery pipelines. These obstacles are evident by the large number of candidate or lead compounds failing to reach clinical trials, significantly due to a lack of efficacy in the disease paradigm of interest and/or the presence of innate chemical toxicity. The consequential compound attrition in discovery pipelines results in added monetary and time costs, potential danger to patients, and a slowed discovery of true therapeutics. The low rate of successful translation calls for improved models that can recapitulate in vivo function in preclinical testing to ensure the removal of toxic compounds earlier in the discovery process, in particular for the assessment of cardiotoxicity, the leading cause of post-market drug withdrawal. With recent advances in the development of human Inducible pluripotent stem cell derived cardiomyocytes (iPSC-CMs), novel compounds can be assessed with better disease relevance while more accurately assessing human safety. In this review, we discuss the utility of iPSC-CMs in preclinical testing by taking advantage of the inherent ability to mimic CMs in vivo. We explore the similarities and differences in electrophysiology, calcium handling, cellular signaling, contractile machinery, and metabolism between iPSC-CMs and adult CMs as these complex coordinated functions directly relate to toxicity evaluation. We will highlight considerations when using iPSC-CMs, such as maturation protocols, to ensure a more representative phenotype of the adult human CM, and how different populations of CMs can affect results in compound testing.

Ultra-High-Frequency ECG in Cardiac Pacing and Cardiac Resynchronization Therapy: From Technical Concept to Clinical Application.

Identifying electrical dyssynchrony is crucial for cardiac pacing and cardiac resynchronization therapy (CRT). The ultra-high-frequency electrocardiography (UHF-ECG) technique allows instantaneous dyssynchrony analyses with real-time visualization. This review explores the physiological background of higher frequencies in ventricular conduction and the translational evolution of UHF-ECG in cardiac pacing and CRT. Although high-frequency components were studied half a century ago, their exploration in the dyssynchrony context is rare. UHF-ECG records ECG signals from eight precordial leads over multiple beats in time. After initial conceptual studies, the implementation of an instant visualization of ventricular activation led to clinical implementation with minimal patient burden. UHF-ECG aids patient selection in biventricular CRT and evaluates ventricular activation during various forms of conduction system pacing (CSP). UHF-ECG ventricular electrical dyssynchrony has been associated with clinical outcomes in a large retrospective CRT cohort and has been used to study the electrophysiological differences between CSP methods, including His bundle pacing, left bundle branch (area) pacing, left ventricular septal pacing and conventional biventricular pacing. UHF-ECG can potentially be used to determine a tailored resynchronization approach (CRT through biventricular pacing or CSP) based on the electrical substrate (true LBBB vs. non-specified intraventricular conduction delay with more distal left ventricular conduction disease), for the optimization of CRT and holds promise beyond CRT for the risk stratification of ventricular arrhythmias.

Sex differences in atrial electrophysiology: IK1 is a major factor that is modulated by sex hormones

Sex differences in atrial electrophysiology: IK1 is a major factor that is modulated by sex hormones

Processing abnormalities in monetary outcome evaluations among male individuals with opioid use disorder: evidence from feedback-related negativity

ABSTRACT Background: Numerous studies have highlighted the pivotal role of alterations in the monetary reward system in the development and maintenance of substance use disorder (SUD). Although these alterations have been well documented in various forms of SUD, the electrophysiological mechanisms specific to opioid use disorder (OUD) remain underexplored. Understanding these mechanisms is critical for developing targeted interventions and advancing theories of addiction specific to opioid use. Objectives: To explore abnormalities in monetary reward outcome processing in males with OUD. We hypothesized that control individuals would show higher feedback-related negativity (FRN) to losses, unlike those in the OUD group, where FRN to losses and gains would not differ significantly. Methods: Fifty-seven participants (29 male individuals with OUD [heroin] and 28 male controls) were evaluated. A combination of the monetary incentive delay task (MIDT) and event-related potential (ERP) technology was used to investigate electrophysiological differences in monetary reward feedback processing between the OUD and healthy control groups. Results: We observed a significant interaction between group (control vs. OUD) and monetary outcome (loss vs. gain), indicated by p < .05 and η2 p = 0.116. Specifically, control participants showed stronger negative FRN to losses than gains (p < .05), unlike the OUD group (p > .05). Conclusion: This study’s FRN data indicate that males with OUD show altered processing of monetary rewards, marked by reduced sensitivity to loss. These findings offer electrophysiological insights into why males with OUD may pursue drugs despite potential economic downsides.

Rhythmic Attention and ADHD: A Narrative and Systematic Review.

In recent decades, a growing body of evidence has confirmed the existence of rhythmic fluctuations in attention, but the effect of inter-individual variations in these attentional rhythms has yet to be investigated. The aim of this review is to identify trends in the attention deficit/hyperactivity disorder (ADHD) literature that could be indicative of between-subject differences in rhythmic attention. A narrative review of the rhythmic attention and electrophysiological ADHD research literature was conducted, and the commonly-reported difference in slow-wave power between ADHD subjects and controls was found to have the most relevance to an understanding of rhythmic attention. A systematic review of the literature examining electrophysiological power differences in ADHD was then conducted to identify studies with conditions similar to those utilised in the rhythmic attention research literature. Fifteen relevant studies were identified and reviewed. The most consistent finding in the studies reviewed was for no spectral power differences between ADHD subjects and controls. However, the strongest trend in the studies reporting power differences was for higher power in the delta and theta frequency bands and lower power in the alpha band. In the context of rhythmic attention, this trend is suggestive of a slowing in the frequency and/or increase in the amplitude of the attentional oscillation in a subgroup of ADHD subjects. It is suggested that this characteristic electrophysiological modulation could be indicative of a global slowing of the attentional rhythm and/or an increase in the rhythmic recruitment of neurons in frontal attention networks in individuals with ADHD.

Supplemental Material for Error Processing in Young Adulthood: Age-Related Differences in Electrophysiology and Behavioral Performance

Supplemental Material for Error Processing in Young Adulthood: Age-Related Differences in Electrophysiology and Behavioral Performance

Electrophysiological Analyses of Human Dorsal Root Ganglia and Human Induced Pluripotent Stem Cell-derived Sensory Neurons From Male and Female Donors

Human induced pluripotent stem cell-derived sensory neurons (hiPSC-SNs) and human dorsal root ganglia neurons (hDRG-N) are popular tools in the field of pain research; however, few groups make use of both approaches. For screening and analgesic validation purposes, important characterizations can be determined of the similarities and differences between hDRG-N and hiPSC-SNs. This study focuses specifically on the electrophysiology properties of hDRG-N in comparison to hiPSC-SNs. We also compared hDRG-N and hiPSC-SNs from both male and female donors to evaluate potential sex differences. We recorded neuronal size, rheobase, resting membrane potential, input resistance, and action potential waveform properties from 83 hiPSCs-SNs (2 donors) and 108 hDRG-N neurons (8 donors). We observed several statistically significant electrophysiological differences between hDRG-N and hiPSC-SNs, such as size, rheobase, input resistance, and several action potential waveform properties. Correlation analysis also revealed many properties that were positively or negatively correlated, some of which were differentially correlated between hDRG-N and hiPSC-SNs. This study shows several differences between hDRG-N and hiPSC-SNs and allows a better understanding of the advantages and disadvantages of both for use in pain research. We hope this study will be a valuable resource for pain researchers considering the use of these human in vitro systems for mechanistic studies and/or drug development projects. PerspectivehiPSC-SNs and hDRG-N are popular tools in the field of pain research. This study allows for a better functional understanding of the pros and cons of both tools.

Emotional processing deficits in individuals with problematic pornography use: Unpleasant bias and pleasant blunting.

A growing body of evidence indicates a connection between emotional processes and the emergence and progression of addiction. However, scant research has examined the involvement of emotional processing within the framework of problematic pornography use (PPU). This study aimed to examine the electrophysiological and subjective differences in emotional processing between male individuals with PPU and healthy controls (HCs) following exposure to everyday affective images. Event-related potentials (ERPs) were recorded from 42 PPU participants (mean age = 20.14 years, SD = 1.35) and 45 HCs (mean age = 20.04 years, SD = 1.45) during an oddball task, in which unpleasant, pleasant, and neutral images were presented as deviant stimuli, while a neutral kettle image served as the standard stimulus. The Self-Assessment Manikin (SAM) was employed to assess participants' subjective experience on the dimensions of valence and arousal. Regarding subjective measures of emotion, individuals with PPU reported lower valence ratings for unpleasant images compared to HCs. In terms of electrophysiological measures of emotion, PPU participants reported larger P2 amplitudes for unpleasant pictures compared to both pleasant and neutral pictures. Moreover, HCs showed enhanced P3 amplitudes in response to pleasant images compared to neutral images, whereas this effect was not observed in PPU participants. These findings indicate that individuals with PPU may display deficits in emotional processing characterized by enhanced responsiveness to negative stimuli and attenuated responsiveness to positive stimuli. The heightened sensitivity to negative stimuli may contribute to the inclination of individuals with PPU to engage in pornography as a coping mechanism for stress regulation. Conversely, their diminished sensitivity to positive stimuli presents a challenge in seeking alternative natural rewards to counter potentially addictive behaviors.

Functionally Distinct Circuits Are Linked by Heterocellular Electrical Synapses in the Thalamic Reticular Nucleus.

The thalamic reticular nucleus (TRN) inhibits sensory thalamocortical relay neurons and is a key regulator of sensory attention as well as sleep and wake states. Recent developments have identified two distinct genetic subtypes of TRN neurons, calbindin-expressing (CB) and somatostatin-expressing (SOM) neurons. These subtypes differ in localization within the TRN, electrophysiological properties, and importantly, targeting of thalamocortical relay channels. CB neurons send inhibition to and receive excitation from first-order thalamic relay nuclei, while SOM neurons send inhibition to and receive excitation from higher-order thalamic areas. These differences create distinct channels of information flow. It is unknown whether TRN neurons form electrical synapses between SOM and CB neurons and consequently bridge first-order and higher-order thalamic channels. Here, we use GFP reporter mice to label and record from CB-expressing and SOM-expressing TRN neurons. We confirm that GFP expression properly differentiates TRN subtypes based on electrophysiological differences, and we identified electrical synapses between pairs of neurons with and without common GFP expression for both CB and SOM types. That is, electrical synapses link both within and across subtypes of neurons in the TRN, forming either homocellular or heterocellular synapses. Therefore, we conclude that electrical synapses within the TRN provide a substrate for functionally linking thalamocortical first-order and higher-order channels within the TRN.

Different responses of mice and rats hippocampus CA1 pyramidal neurons to in vitro and in vivo-like inputs.

The fundamental role of any neuron within a network is to transform complex spatiotemporal synaptic input patterns into individual output spikes. These spikes, in turn, act as inputs for other neurons in the network. Neurons must execute this function across a diverse range of physiological conditions, often based on species-specific traits. Therefore, it is crucial to determine the extent to which findings can be extrapolated between species and, ultimately, to humans. In this study, we employed a multidisciplinary approach to pinpoint the factors accounting for the observed electrophysiological differences between mice and rats, the two species most used in experimental and computational research. After analyzing the morphological properties of their hippocampal CA1 pyramidal cells, we conducted a statistical comparison of rat and mouse electrophysiological features in response to somatic current injections. This analysis aimed to uncover the parameters underlying these distinctions. Using a well-established computational workflow, we created ten distinct single-cell computational models of mouse CA1 pyramidal neurons, ready to be used in a full-scale hippocampal circuit. By comparing their responses to a variety of somatic and synaptic inputs with those of rat models, we generated experimentally testable hypotheses regarding species-specific differences in ion channel distribution, kinetics, and the electrophysiological mechanisms underlying their distinct responses to synaptic inputs during the behaviorally relevant Gamma and Sharp-Wave rhythms.

Sex Differences in Mouse Cardiac Electrophysiology Revealed by Simultaneous Imaging of Excitation-Contraction Coupling.

Males and females differ in the basic anatomy and physiology of the heart. Sex differences are evident in cardiac repolarization in humans; women have longer corrected QT and JT intervals. However, the molecular mechanisms that lead to these differences are incompletely understood. Here, we present that, like in humans, sex differences in QT and JT intervals exist in mouse models; female mice had longer corrected QT and JT intervals compared with age-matched males. To further understand the molecular underpinning of these sex differences, we developed a novel technology using fluorescent confocal microscopy that allows the simultaneous visualization of action potential, Ca2+ transients, and contractions in isolated cardiomyocytes at a high temporal resolution. From this approach, we uncovered that females at baseline have increased action potential duration, decreased Ca2+ release and reuptake rates, and decreased contraction and relaxation velocities compared with males. Additionally, males had a shorter overall time from action potential onset to peak contraction. In aggregate, our studies uncovered male and female differences in excitation-contraction coupling that account for differences observed in the EKG. Overall, a better understanding of sex differences in electrophysiology is essential for equitably treating cardiac disease.

Genetic heterogeneity within a consanguineous family involving TTPA and SETX genes

Autosomal recessive cerebellar ataxias (ARCA) constitute a highly heterogeneous group of progressive neurodegenerative disorders that typically occur prior to adulthood. Despite some clinical resemblance between these disorders, different genes are involved. We report in this study four Tunisian patients belonging to the same large consanguineous family, sharing autosomal recessive cerebellar ataxia phenotypes but with clinical, biological, electrophysiological, and radiological differences leading to the diagnosis of two distinct ARCA caused by two distinct gene defects. Two of our patients presented ataxia with the vitamin E deficiency (AVED) phenotype, and the other two presented ataxia with oculo-motor apraxia 2 (AOA2). Genetic testing confirmed the clinical diagnosis by the detection of a frameshift c.744delA pathogenic variant in the TTPA gene, which is the most frequent in Tunisia, and a new variant c.1075dupT in the SETX gene. In Tunisia, data suggest that genetic disorders are common. The combined effects of the founder effect and inbreeding, added to genetic drift, may increase the frequency of detrimental rare disorders. The genetic heterogeneity observed in this family highlights the difficulty of genetic counseling in an inbred population. The examination and genetic testing of all affected patients, not just the index patient, is essential to not miss a treatable ataxia such as AVED, as in the case of this family.