BackgroundSpinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein resulting in neuropathology including mutant ataxin-1... Show moreBackgroundSpinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein resulting in neuropathology including mutant ataxin-1 protein aggregation, aberrant neurodevelopment, and mitochondrial dysfunction. ObjectivesIdentify SCA1-relevant phenotypes in patient-specific fibroblasts and SCA1 induced pluripotent stem cells (iPSCs) neuronal cultures. MethodsSCA1 iPSCs were generated and differentiated into neuronal cultures. Protein aggregation and neuronal morphology were evaluated using fluorescent microscopy. Mitochondrial respiration was measured using the Seahorse Analyzer. The multi-electrode array (MEA) was used to identify network activity. Finally, gene expression changes were studied using RNA-seq to identify disease-specific mechanisms. ResultsBioenergetics deficits in patient-derived fibroblasts and SCA1 neuronal cultures showed altered oxygen consumption rate, suggesting involvement of mitochondrial dysfunction in SCA1. In SCA1 hiPSC-derived neuronal cells, nuclear and cytoplasmic aggregates were identified similar in localization as aggregates in SCA1 postmortem brain tissue. SCA1 hiPSC-derived neuronal cells showed reduced dendrite length and number of branching points while MEA recordings identified delayed development in network activity in SCA1 hiPSC-derived neuronal cells. Transcriptome analysis identified 1050 differentially expressed genes in SCA1 hiPSC-derived neuronal cells associated with synapse organization and neuron projection guidance, where a subgroup of 151 genes was highly associated with SCA1 phenotypes and linked to SCA1 relevant signaling pathways. ConclusionsPatient-derived cells recapitulate key pathological features of SCA1 pathogenesis providing a valuable tool for the identification of novel disease-specific processes. This model can be used for high throughput screenings to identify compounds, which may prevent or rescue neurodegeneration in this devastating disease. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Show less
Berg, M. van den; Toen, D.; Verhoye, M.; Keliris, G.A. 2023
Alzheimer's disease (AD) is a severe neurodegenerative disorder caused by the accumulation of toxic proteins, amyloid-beta (A beta) and tau, which eventually leads to dementia. Disease-modifying... Show moreAlzheimer's disease (AD) is a severe neurodegenerative disorder caused by the accumulation of toxic proteins, amyloid-beta (A beta) and tau, which eventually leads to dementia. Disease-modifying therapies are still lacking, due to incomplete insights into the neuropathological mechanisms of AD. Synaptic dysfunction is known to occur before cognitive symptoms become apparent and recent studies have demonstrated that imbalanced synaptic signaling drives the progression of AD, suggesting that early synaptic dysfunction could be an interesting therapeutic target. Synaptic dysfunction results in altered oscillatory activity, which can be detected with electroencephalography and electrophysiological recordings. However, the majority of these studies have been performed at advanced stages of AD, when extensive damage and cognitive symptoms are already present. The current study aimed to investigate if the hippocampal oscillatory activity is altered at pre-plaque stages of AD. The rats received stereotactic surgery to implant a laminar electrode in the CA1 layer of the right hippocampus. Electrophysiological recordings during two consecutive days in an open field were performed in 4-5-month-old TgF344-AD rats when increased concentrations of soluble A beta species were observed in the brain, in the absence of A beta-plaques. We observed a decreased power of high theta oscillations in TgF344-AD rats compared to wild-type littermates. Sharp wave-ripple (SWR) analysis revealed an increased SWR power and a decreased duration of SWR during quiet wake in TgF344-AD rats. The alterations in properties of SWR and the increased power of fast oscillations are suggestive of neuronal hyperexcitability, as has been demonstrated to occur during presymptomatic stages of AD. In addition, decreased strength of theta-gamma coupling, an important neuronal correlate of memory encoding, was observed in the TgF344-AD rats. Theta-gamma phase amplitude coupling has been associated with memory encoding and the execution of cognitive functions. Studies have demonstrated that mild cognitive impairment patients display decreased coupling strength, similar to what is described here. The current study demonstrates altered hippocampal network activity occurring at pre-plaque stages of AD and provides insights into prodromal network dysfunction in AD. The alterations observed could aid in the detection of AD during presymptomatic stages. Show less
Hu, M.H.Y.; Frimat, J.P.; Rijkers, K.; Schijns, O.E.M.G.; Maagdenberg, A.M.J.M. van den; Dings, J.T.A.; ... ; Hoogland, G. 2023
A growing societal awareness is calling upon scientists to reconsider the use of animals in research, which stimulates the development of translational in vitro models. The physiological and... Show moreA growing societal awareness is calling upon scientists to reconsider the use of animals in research, which stimulates the development of translational in vitro models. The physiological and architectural interactions between different cell types within an organ present a challenge to these models, particularly for a complex organ such as the brain. Thus far, in vitro brain models mostly consist of a single cell type and demonstrate little predictive value. Here, we present a co-culture of an epileptic human neocortical biopsy on a layer of human induced pluripotent stem cell (hiPSC)-derived cortical neurons. The activity of the cortical neurons was recorded by a 120-electrode multi-electrode array. Recordings were obtained at 0, 3, and 6 days after assembly and compared to those obtained from cortical neurons without a biopsy. On all three recording days, the hybrid model displayed a firing rate, burst behavior, number of isolated spikes, inter-spike interval, and network bursting pattern that aligns with the characteristics of an epileptic network as reported by others. Thus, this novel model may be a non-animal, translational alternative for testing new therapies up to six days after resection. Show less
Shared decision making (SDM) has been advocated to improve patient care, patient decision acceptance, patient-provider communication, patient motivation, adherence, and patient reported outcomes.... Show moreShared decision making (SDM) has been advocated to improve patient care, patient decision acceptance, patient-provider communication, patient motivation, adherence, and patient reported outcomes. Documentation of SDM is endorsed in several society guidelines and is a condition of reimbursement for selected cardiovascular and cardiac arrhythmia procedures. However, many clinicians argue that SDM already occurs with clinical encounter discussions or the process of obtaining informed consent and note the additional imposed workload of using and documenting decision aids without validated tools or evidence that they improve clinical outcomes. In reality, SDM is a process and can be done without decision tools, although the process may be variable. Also, SDM advocates counter that the low-risk process of SDM need not be held to the high bar of demonstrating clinical benefit and that increasing the quality of decision making should be sufficient. Our review leverages a multidisciplinary group of experts in cardiology, cardiac electrophysiology, epidemiology, and SDM, as well as a patient advocate. Our goal is to examine and assess SDM methodology, tools, and available evidence on outcomes in patients with heart rhythm disorders to help determine the value of SDM, assess its possible impact on electrophysiological procedures and cardiac arrhythmia management, better inform regulatory requirements, and identify gaps in knowledge and future needs. Show less
The field of electrophysiology (EP) in paediatric cardiology patients and adults with congenital heart disease is complex and rapidly growing. The current recommendations for diagnostic and... Show moreThe field of electrophysiology (EP) in paediatric cardiology patients and adults with congenital heart disease is complex and rapidly growing. The current recommendations for diagnostic and invasive electrophysiology of the working group for Cardiac Dysrhythmias and Electrophysiology of the Association for European Paediatric and Congenital Cardiology acknowledges the diveristy of European countries and centers. These training recommendations can be fulfilled in a manageable period of time, without compromising the quality of training required to become an expert in the field of paediatric and congenital EP and are for trainees undergoing or having completed accredited paediatric cardiologist fellowship. Three levels of expertise, the training for General paediatric cardiology EP, for non-invasive EP and invasive EP have been defined. This Association for European EP curriculum describes the theoretical and practicsal knowledge in clinical EP; catheter ablation, cardiac implantable electronic devices, inherited arrhythmias and arrhythmias in adults with congenital heart defects for the 3 levels of expertise. Show less
Perenboom, M.J.L.; Schenke, M.; Ferrari, M.D.; Terwindt, G.M.; Maagdenberg, A.M.J.M. van den; Tolner, E.A. 2020
Migraine patients often report (inter)ictal hypersensitivity to light, but the underlying mechanisms remain an enigma. Both hypo- and hyperresponsivity of the visual network have been reported,... Show moreMigraine patients often report (inter)ictal hypersensitivity to light, but the underlying mechanisms remain an enigma. Both hypo- and hyperresponsivity of the visual network have been reported, which may reflect either intra-individual dynamics of the network or large inter-individual variation in the measurement of human visual evoked potential data. Therefore, we studied visual system responsivity in freely behaving mice using combined epidural electroencephalography and intracortical multi-unit activity to reduce variation in recordings and gain insight into visual cortex dynamics. For better clinical translation, we investigated transgenic mice that carry the human pathogenic R192Q missense mutation in the alpha(1A) subunit of voltage-gated Ca(V)2.1 Ca2+ channels leading to enhanced neurotransmission and familial hemiplegic migraine type 1 in patients. Visual evoked potentials were studied in response to visual stimulation paradigms with flashes of light. Following intensity-dependent visual stimulation, FHM1 mutant mice displayed faster visual evoked potential responses, with lower initial amplitude, followed by less pronounced neuronal suppression compared to wild-type mice. Similar to what was reported for migraine patients, frequency-dependent stimulation in mutant mice revealed enhanced photic drive in the EEG beta-gamma band. The frequency-dependent increases in visual network responses in mutant mice may reflect the context-dependent enhancement of visual cortex excitability, which could contribute to our understanding of sensory hypersensitivity in migraine. Show less
Fienieg, B.; Hassing, G.J.; Wall, H.E.C. van der; Westen, G.J.P. van; Kemme, M.J.B.; Adiyaman, A.; ... ; Gal, P. 2020
Background Previous studies reported that hypo- and hyperthermia are associated with several atrial and ventricular electrocardiographical parameters, including corrected QT (QTc) interval.... Show moreBackground Previous studies reported that hypo- and hyperthermia are associated with several atrial and ventricular electrocardiographical parameters, including corrected QT (QTc) interval. Enhanced characterization of variations in QTc interval and normothermic body temperature aids in better understanding the underlying mechanism behind drug induced QTc interval effects. The analysis' objective was to investigate associations between body temperature and electrocardiographical parameters in normothermic healthy volunteers.Methods Data from 3023 volunteers collected at our center were retrospectively analyzed. Subjects were considered healthy after review of collected data by a physician, including a normal tympanic body temperature (35.5-37.5 degrees C) and in sinus rhythm. A linear multivariate model with body temperature as a continuous was performed. Another multivariate analysis was performed with only the QT subintervals as independent variables and body temperature as dependent variable.Results Mean age was 33.8 +/- 17.5 years and mean body temperature was 36.6 +/- 0.4 degrees C. Body temperature was independently associated with age (standardized coefficient [SC] = -0.255, P < .001), female gender (SC = +0.209, P < .001), heart rate (SC = +0.231, P < .001), P-wave axis (SC = -0.051, P < .001), J-point elevation in lead V4 (SC = -0.121, P < .001), and QTcF duration (SC = -0.061, P = .002). In contrast, other atrial and atrioventricular (AV) nodal parameters were not independently associated with body temperature. QT subinterval analysis revealed that only QRS duration (SC = -0.121, P < .001) was independently associated with body temperature.Conclusion Body temperature in normothermic healthy volunteers was associated with heart rate, P-wave axis, J-point amplitude in lead V4, and ventricular conductivity, the latter primarily through prolongation of the QRS duration. Show less
Fienieg, B.; Hassing, G.J.; Wall, H.E.C. van der; Westen, G.J.P. van; Kemme, M.J.B.; Adiyaman, A.; ... ; Gal, P. 2020
BACKGROUNDPrevious studies reported that hypo- and hyperthermia are associated with several atrial and ventricular electrocardiographical parameters, including corrected QT (QTc) interval. Enhanced... Show moreBACKGROUNDPrevious studies reported that hypo- and hyperthermia are associated with several atrial and ventricular electrocardiographical parameters, including corrected QT (QTc) interval. Enhanced characterization of variations in QTc interval and normothermic body temperature aids in better understanding the underlying mechanism behind drug induced QTc interval effects. The analysis' objective was to investigate associations between body temperature and electrocardiographical parameters in normothermic healthy volunteers.METHODSData from 3023 volunteers collected at our center were retrospectively analyzed. Subjects were considered healthy after review of collected data by a physician, including a normal tympanic body temperature (35.5-37.5°C) and in sinus rhythm. A linear multivariate model with body temperature as a continuous was performed. Another multivariate analysis was performed with only the QT subintervals as independent variables and body temperature as dependent variable.RESULTSMean age was 33.8 ± 17.5 years and mean body temperature was 36.6 ± 0.4°C. Body temperature was independently associated with age (standardized coefficient [SC] = -0.255, P < .001), female gender (SC = +0.209, P < .001), heart rate (SC = +0.231, P < .001), P-wave axis (SC = -0.051, P < .001), J-point elevation in lead V4 (SC = -0.121, P < .001), and QTcF duration (SC = -0.061, P = .002). In contrast, other atrial and atrioventricular (AV) nodal parameters were not independently associated with body temperature. QT subinterval analysis revealed that only QRS duration (SC = -0.121, P < .001) was independently associated with body temperature.CONCLUSIONBody temperature in normothermic healthy volunteers was associated with heart rate, P-wave axis, J-point amplitude in lead V4, and ventricular conductivity, the latter primarily through prolongation of the QRS duration. Show less
Background:The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF).... Show moreBackground:The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.Methods:Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and approximate to 230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies.Results:We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk.Conclusions:Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF. Show less
Venlet, J.; Tao, Q.; Graaf, M.A. de; Glashan, C.A.; Silva, M.D.; Geest, R.J. van der; ... ; Zeppenfeld, K. 2020
OBJECTIVES This study sought to evaluate whether right ventricular (RV) tissue heterogeneity on computed tomography (CT): 1) is associated with conduction delay in arrhythmogenic right ventricular... Show moreOBJECTIVES This study sought to evaluate whether right ventricular (RV) tissue heterogeneity on computed tomography (CT): 1) is associated with conduction delay in arrhythmogenic right ventricular cardiomyopathy (ARVC); and 2) distinguishes patients with ARVC from those with exercise-induced arrhythmogenic remodeling (EIAR) and control individuals.BACKGROUND ARVC is characterized by fibrofatty replacement, related to conduction delay and ventricular tachycardiac. Distinguishing ARVC from acquired, EIAR is challenging.METHODS Patients with ARVC or EIAR and combined endocardial-epicardiat electroanatomic voltage mapping for VT ablation with CT integration were enrolled. Patients without structural heart disease served as control individuals. Tissue heterogeneity on CT (CT heterogeneity) was automatically quantified within the 2-mm subepicardium of the entire RV free wall at normal sites and tow voltage sites harboring late potentials (LP+) in ARVC/EIAR.RESULTS Seventeen patients with ARVC (15 mates; age: 50 17 years), 9 patients with EIAR (7 males; age: 45 14 years) and 17 control individuals (14 males; age: 50 +/- 15 years) were enrolled. Of 5,215 ARVC mapping points, 560 (11%) showed LP+ . CT heterogeneity was higher at sites with LP-i compared to normal sites (median: 31 HU/mm; IQR: 23 to 46 HU/mm vs. median: 16 HU/mm; IQR: 13 to 21 HU/mm; p < 0.001). The optimal CT heterogeneity cutoff for detection of LP+ was 25 HU/mm (area under the curve [AUG 0.80; sensitivity: 72%; specificity: 78%). Overall CT heterogeneity allowed highly accurate differentiation between patients with ARVC and control individuals (AUC: 0.97; sensitivity: 100%; specificity: 82%) and between ARVC and EIAR (AUC: 0.78; sensitivity: 65%; spedficity: 89%).CONCLUSIONS In patients with ARVC, tissue heterogeneity on CT can be used to identify LP+ as a surrogate for ventricular tachycardia substrate. The overall tissue heterogeneity on CT allows the distinguishing of patients with ARVC from those with EIAR and control individuals. (C) 2020 by the American College of Cardiology Foundation. Show less
Animal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived cardiomyocytes ... Show moreAnimal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, we quantified changes in contractility, voltage, and/or Ca2+ handling in 2D monolayers or 3D engineered heart tissues (EHT5). Protocols were unified via a drug training set, allowing subsequent blinded multicenter evaluation of drugs with known positive, negative, or neutral inotropic effects. Accuracy ranged from 44% to 85% across the platform-cell configurations, indicating the need to refine test conditions. This was achieved by adopting approaches to reduce signal-to-oise ratio, reduce spontaneous beat rate to <= 1 Hz or enable chronic testing, improving accuracy to 85% for monolayers and 93% for EHT5. Contraction amplitude was a good predictor of negative inotropes across all the platform-cell configurations and of positive inotropes in the 3D EHT5. Although contraction- and relaxation-time provided confirmatory readouts forpositive inotropes in 3D EHT5, these parameters typically served as the primary source of predictivity in 2D. The reliance of these "secondary" parameters to inotropy in the 2D systems was not automatically intuitive and may be a quirk of hiPSC-CMs, hence require adaptations in interpreting the data from this model system. Of the platform-cell configurations, responses in EHTs aligned most closely to the free therapeutic plasma concentration. This study adds to the notion that hiPSC-CMs could add value to drug safety evaluation. Show less
Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have... Show moreCortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1-10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K+] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies. Show less
