Critical Circuit Research Articles

Functional PET/MRI reveals active inhibition of neuronal activity during optogenetic activation of the nigrostriatal pathway.

The dopaminergic system is a central component of the brain's neurobiological framework, governing motor control and reward responses and playing an essential role in various brain disorders. Within this complex network, the nigrostriatal pathway represents a critical circuit for dopamine neurotransmission from the substantia nigra to the striatum. However, stand-alone functional magnetic resonance imaging is unable to study the intricate interplay between brain activation and its molecular underpinnings. In our study, the use of a functional [fluorine-18]2-fluor-2-deoxy-d-glucose positron emission tomography approach, simultaneously with blood oxygen level-dependent functional magnetic resonance imaging, provided an important insight that demonstrates an active suppression of the nigrostriatal activity during optogenetic stimulation. This result increases our understanding of the molecular mechanisms of brain function and provides an important perspective on how dopamine influences hemodynamic responses in the brain.

Assembloid models of cell-cell interaction to study tissue and disease biology.

Neurodevelopment involves the migration, projection, and integration of various cell types across different regions of the nervous system. Assembloids are self-organizing systems formed by the integration of multiple organoids or cell types. Here, we outline the generation and application of assembloids. We illustrate how assembloids recapitulate critical neurodevelopmental steps, like migration, axon projection, and circuit formation, and how they are starting to provide biological insights into neuropsychiatric disorders. Additionally, we review how assembloids can be used to study properties emerging from cell-cell interactions within non-neural tissues. Overall, assembloid platforms represent a powerful tool for discovering human biology and developing therapeutics.

Noise Analysis and Suppression Methods for the Front-End Readout Circuit of a Microelectromechanical Systems Gyroscope

Circuit noise is a critical factor that affects the performances of an MEMS gyroscope. Therefore, it is essential to analyze and suppress the noises in the key analog circuits, which are the main noise sources. This study presents an optimized front-end readout circuit and noise suppression methods. First, the noise analysis of the front-end readout circuit is carried out with theoretical derivation to clarify the main noise contributors. To suppress the output noise, an improved readout circuit based on the T-resistor networks is proposed, and the corresponding noise equation is derived in detail. In addition, the noise analysis of the critical circuits of the detection and control system, such as the inverting amplifiers, the first-order low-pass filters, and the first-order high-pass filters, is carried out, and the noise suppression strategy with the optimization of the resistances and is proposed. Taking the inverting amplifier as an example, the theoretical derivation is verified by measuring and comparing the output noises of different resistance schemes. In addition, the output noises of the gyroscope before and after circuit optimization are measured. Experimental results demonstrate that the output noise with the circuit optimization is reduced from 60 μV/Hz1/2 to 30 μV/Hz1/2 and the bias instability is reduced from 3.8 deg/h to 1.38 deg/h. In addition, the ARW is significantly improved from 0.035 deg/h1/2 to 0.018 deg/h1/2, which indicates that the proposed noise analysis and suppression methods are effective and feasible.

Extracellular purines in lung endothelial permeability and pulmonary diseases.

The purinergic signaling system is an evolutionarily conserved and critical regulatory circuit that maintains homeostatic balance across various organ systems and cell types by providing compensatory responses to diverse pathologies. Despite cardiovascular diseases taking a leading position in human morbidity and mortality worldwide, pulmonary diseases represent significant health concerns as well. The endothelium of both pulmonary and systemic circulation (bronchial vessels) plays a pivotal role in maintaining lung tissue homeostasis by providing an active barrier and modulating adhesion and infiltration of inflammatory cells. However, investigations into purinergic regulation of lung endothelium have remained limited, despite widespread recognition of the role of extracellular nucleotides and adenosine in hypoxic, inflammatory, and immune responses within the pulmonary microenvironment. In this review, we provide an overview of the basic aspects of purinergic signaling in vascular endothelium and highlight recent studies focusing on pulmonary microvascular endothelial cells and endothelial cells from the pulmonary artery vasa vasorum. Through this compilation of research findings, we aim to shed light on the emerging insights into the purinergic modulation of pulmonary endothelial function and its implications for lung health and disease.

Variable-Frequency Control for Totem-Pole Bridgeless Power Factor Correction Converter to Achieve Zero-Voltage Switching Without Zero-Crossing Detection Circuits

The totem-pole bridgeless power factor correction (PFC) converter, known for its advantages including simple topology, capability for zero-voltage switching (ZVS), and low common mode interference, presents an opportunity to enhance the efficiency and environmental friendliness of power systems. However, these converters have issues such as ZVS, requiring zero-crossing detection (ZCD) under circuits’ critical continuous mode (CRM) or additional auxiliary resonant circuits, resulting in increased circuit costs and control complexity. Therefore, this paper proposes a variable switching frequency digital control method to achieve ZVS under a wide operating range without ZCD circuits. At the same time, under the premise of ZVS, an interleaved parallel scheme is adopted to further minimize the current ripple and enhance the quality of the current waveform. Finally, an experimental 2 kW two-phase interleaved totem-pole bridgeless PFC converter prototype is designed to verify that the proposed method is correct and effective. The experimental prototype can reach an efficiency of 97.78%.

Sex differences in neural projections of fear memory processing in mice and humans.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

Stimulation of caudal inferior and middle frontal gyri disrupts planning during spoken interaction

Turn-taking is a central feature of conversation across languages and cultures.1,2,3,4 This key social behavior requires numerous sensorimotor and cognitive operations1,5,6 that can be organized into three general phases: comprehension of a partner's turn, preparation of a speaker's own turn, and execution of that turn. Using intracranial electrocorticography, we recently demonstrated that neural activity related to these phases is functionally distinct during turn-taking.7 In particular, networks active during the perceptual and articulatory stages of turn-taking consisted of structures known to be important for speech-related sensory and motor processing,8,9,10,11,12,13,14,15,16,17 while putative planning dynamics were most regularly observed in the caudal inferior frontal gyrus (cIFG) and the middle frontal gyrus (cMFG). To test if these structures are necessary for planning during spoken interaction, we used direct electrical stimulation (DES) to transiently perturb cortical function in neurosurgical patient-volunteers performing a question-answer task.7,18,19 We found that stimulating the cIFG and cMFG led to various response errors9,13,20,21 but not gross articulatory deficits, which instead resulted from DES of structures involved in motor control8,13,20,22 (e.g., the precentral gyrus). Furthermore, perturbation of the cIFG and cMFG delayed inter-speaker timing-consistent with slowed planning-while faster responses could result from stimulation of sites located in other areas. Taken together, our findingssuggest that the cIFG and cMFG contain critical preparatory circuits that are relevant for interactive language use.

Frontiers and challenges in silicon-based single-photon avalanche diodes and key readout circuits

Single-photon detectors enable the detection of extremely weak light with remarkable temporal precision. This capability provides crucial technological support for precise distance measurements and high-resolution imaging under low-light conditions. Silicon and silicon-based germanium single-photon detectors can operate in a wide spectrum from the visible to the near-infrared region, and exhibit fundamental advantages without needing heterogeneous integration. In recent years, there has been continuous progress in the miniaturization of silicon-based single-photon diodes and corresponding read-out circuits. The integration scheme of 3D stacking has enabled the optimization of the devices and circuits at different process nodes. This evolution has comprehensively enhanced system volumes and performances. Thus, detection systems and applications of silicon-based single-photon technology continue to expand. In this paper, we review the structural evolution, performance characterization, manufacturing processes, and analog front-end circuits of single-photon detectors based on CMOS/CIS technology and silicon-based germanium avalanche photodiodes. Additionally, we provide an overview of the critical circuits in typical application scenarios.

Trauma, early life stress, and mindfulness in adulthood

This article is a review that was inspired by recent studies investigating the effects of childhood trauma or early life stress (ELS) and mindfulness in adulthood. One recent study found that some forms of abuse and neglect led to higher scores in several subscales of a self-report measure of mindfulness. The authors concluded that some forms of ELS can help cultivate certain aspects of mindfulness in adulthood. However, and in contrast to this recent finding, much of the extant literature investigating ELS and trauma are linked to emotional dysregulation, alexithymia, and a host of psychopathologies in adulthood which makes the results of this study surprising. Central to the mindfulness literature is cultivating an open, non-reactive, or non-judgment awareness of inner experiences which are important for emotional regulation. In this paper, I review some of the effects of trauma or ELS on critical neural circuits linked to mindfulness, interoception, attachment, and alexithymia which I hope may clarify some of the conflicting findings from this study and throughout the literature and provide additional context and a framework that may inform research investigating these two constructs going forward.

Is intraoperative mapping of music performance mandatory to preserve skills in professional musicians? Awake surgery for lower-grade glioma conducted from a meta-networking perspective.

In surgery for lower-grade glioma (LGG) in professional musicians, for whom preserving music ability is essential, a critical question has emerged, namely, is it mandatory to include music performance during awake mapping, as proposed in several reports? In fact, music ability is subserved by a mosaic of interactive cognitive and emotional processes that rest on several networks. Therefore, from a meta-network perspective, the authors investigated whether an integrated multimodal monitoring of these cognitive and emotional functions during stimulation mapping could be efficient in maintaining musical skill. Indeed, it could be difficult for a patient to play a musical instrument in the surgical setting in addition to performing other tasks, such as movement and language. An awake mapping-guided resection for LGG without intraoperative music performance was performed in 3 professional musicians. Intraoperative tests were tailored to each patient depending on the critical corticosubcortical circuits surrounding the tumor, including not only sensorimotor or language skills but also higher-order functions with a constant multitasking during the resection. Although music skills were not mapped during surgery, all patients resumed their professional activities, preserving the ability to play music and to perform concerts, to teach and to compose music, or to start learning a new instrument. A connectome-based resection without intraoperative music performance seems effective in achieving maximal glioma removal while preserving crucial networks subserving musical skills, creativity, and music learning. Neurosurgery should evolve toward a meta-networking approach to better understand higher-order functions mediating complex behavior, such as being a professional musician.

Accurate Multi-segment Probability Density Estimation Through Moment Matching

The impact of process variations continues to grow as transistor feature size shrinks. Such variations in transistor parameters lead to variations and unpredictability in circuit output and may ultimately cause them to violate specifications leading to circuit failure. In fact, timely failures in critical circuits may lead to catastrophic failures in the entire chip. As such, statistical modeling of circuit behavior is becoming increasingly important. However, existing statistical circuit simulation approaches fail to accurately and efficiently analyze the high sigma behavior of probabilistic circuit output. To this end, we propose PDM (Piecewise Distribution Model) - a piecewise distribution modeling approach via moment matching using maximum entropy to model the high sigma behavior of analog/mixed-signal (AMS) circuit probability distributions. PDM is independent of the number of input dimensions and matches region specific probabilistic moments which allows for significantly greater accuracy compared to other moment matching approaches. PDM also utilizes Spearman’s rank correlation coefficient to select the optimal approximation for the tail of the distribution. Experiments on a known mathematical distribution and various circuits obtain accurate results up to 4.8 sigma with 2-3 orders of speedup relative to Monte Carlo. PDM also demonstrates better accuracy while compared against other state-of-the-art statistical modeling approaches, such as maximum entropy, importance sampling, and subset simulation.

Chronic Pb exposure impairs learning and memory abilities by inhibiting excitatory projection neuro-circuit of the hippocampus in mice

Lead (Pb) is an environmental neurotoxic metal. Chronic Pb exposure causes behavioral changes in humans and rodents, such as dysfunctional learning and memory. Nevertheless, it is not clear whether Pb exposure disrupts the neural circuit. Thus, here we aim at investigating the effects the chronic Pb exposure on neural-behavioral and neural circuits in mice from prenatal to postnatal day (PND) 63. Pregnant mice and their male offspring were treated with Pb (150 ppm) until postnatal day 63. In this study, several behavior tests and Golgi-Cox staining methods were used to assess spatial memory ability and synaptogenesis. Virus-based tracing systems and immunohistochemistry assays were used to test the relevance of chronic Pb exposure with disrupted neural circuits. The behavioral experiments and Golgi-Cox staining results showed that Pb exposure impaired spatial memory and spine density in mice. The virus tracing results revealed that the Entorhinal cortex (EC) neurons could be directly projected to Cornuammonis 1 (CA1) and Dentate gyrus (DG), forming a critical circuit inhibited, in either a direct or indirect way, by Pb invasion. In addition, excitatory neural input from EC（labeled with CaMKII）to CA1 and DG was significantly attenuated by Pb exposure. In conclusion, our data indicated that Pb significantly impaired the excitatory connections from EC to the hippocampus (CA1 and DG), providing a novel neuro-circuitry basis for Pb neurotoxicity.

Will new brain circuit focused methods (EEG, fMRI etc) lead to more personalized care options?

The advent of new non-invasive (largely EEG and MRI-based) methods for recording the activity of critical brain circuits (frontotemporal and subcortical) and networks (Default Mode, Salience, Central Executive), cross-sectionally and longitudinally, as well as concurrently (EEG and fMRI), has led to a focus on whether such techniques could be used to guide individual treatment selection. While this work has commenced with specific relevance to depression and other mood disorders (Goldstein-Piekarski et al., 2022; Hack et al., 2023; Scangos et al., 2023), there is still much to be learnt and a great need to replicate findings across different cohorts and different research centres.

A co-simulation of superconducting qubit and control electronics for quantum computing.

As the number of qubits in quantum computing increases, the scalability of existing qubit circuit structures and control systems may become insufficient for large-scale expansion and high-fidelity control. To address this challenge, we propose a behavioral-level model of a superconducting qubit and its control electronics, followed by a co-simulation to evaluate their performance. In this paper, we present the modeling process, simulation procedure, and resulting design specifications for the qubit control system. Our co-simulation approach utilizes MATLAB and Simulink, enabling us to derive critical circuit design specifications, such as the required Digital-to-Analog Converter (DAC) resolution, which should be 8 bits or higher, to achieve high-fidelity control. By taking into account factors such as DAC sampling rates, integral and differential nonlinearities, and filter characteristics, we optimize the control system for efficient and accurate qubit manipulation. Our model and simulation approach offer a promising solution to the scalability challenges in quantum computing, providing valuable insights for the design of large-scale superconducting quantum computing systems.

Persistently Present, Yet Invisible? Exploring the Experiences of High-Achieving Black Students in the Greater Toronto Area

Through employing critical race theory, seen-invisibility, and circuits of dispossession as theoretical frames, this article complicates discourses around equity and Black student achievement by examining the underexplored experiences of high-achieving Black Canadian students in the Greater Toronto Area (GTA). Drawing on focus group data with four adolescent participants, the study finds that they experienced violent forms of racialization in their educational environments through a lack of physical, social, and intellectual space to exist as both Black and high-achieving. This rendered them persistently present due to their race, yet invisible in the perceptions of their intellect. Central to this article is an articulation, unpacking, and thus granular analysis of the particular ways that racialization can operate within education systems to still marginalize Black students and erect complex barriers––even when they demonstrate strong academic performance. These emerging insights inform a need for a broader and more holistic understanding of Black Canadian student experiences and a rethinking of intervention and resistance strategies.

Predicting ICD therapy and post-ablation ventricular tachycardia recurrence using cardiac MRI-based advanced computational reentrant pathway analysis

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): EACVI, Netherlands Heart Institute. Background MRI late gadolinium enhancement (LGE) images can provide novel insights about critical pathways through scar but does not assess the vulnerability of these pathways for sustaining scar-mediated ventricular tachycardia (VT). Computational modelling can augment the insights from imaging derived metrics by providing the functional implications of structural anatomy of the substrate. However, current (monodomain) approaches are computationally expensive and may not, by design, extract all critical pathways. Aim This study evaluated the performance of a novel, reaction-Eikonal based, automated reentrant pathway finding algorithm (VITA) to assess the functional viability of critical circuits identified on LGE and non-invasively predict arrhythmic risk in both an ICD and post-ablation cohort recurrence. Methods ADAS LV and custom-made software was used to generate 3D patient-specific ventricular models in a prospective cohort of post-infarct ICD patients (cohort 1, n=40) and a retrospective cohort of 20 post-infarct VT-ablation patients (cohort 2). Our Virtual Induction and Treatment of Arrhythmias (VITA) framework was then applied to comprehensively probe the viability of the scar substrate to sustaining reentrant circuits. VITA metrics, related to the numbers of induced VTs and their corresponding round trip times (RTTs), were compared with appropriate ICD therapy (cohort 1) and VT-recurrence (cohort 2) during follow-up. Results Patients in both cohorts with an event had higher VITA metrics. In cohort 1 (ICD), VITA demonstrated significantly more inducible VTs (6.6±4.2 vs. 4.1±3.4, p = .044), longer mean RTT (116.2±50.9 ms vs. 76.9±42.6 ms, p = .012) and max RTT (194.4±105.1 ms vs. 109.6±78.7, p =.009) in the event group. In addition, Cox-regression demonstrated a significant independent association with an event: induced VTs (HR 1.67; CI 1.04–2.68, p = .03), mean RTT (HR 2.14; CI 1.11–4.12, p = .02), maximum RTT (HR 2.13; CI 1.19–3.81, p = .01). In cohort 2 (VT-ablation), total induced VTs (85±43 vs. 42±27, p = .01) and unique VTs (9±4 vs. 5±4, p = .04) were significantly higher in patients with- compared to patients without recurrence, and were predictive of recurrence with AUC of .820 and .770, respectively. Max RTT demonstrated a trend towards significance 293 ± 90 ms vs. 200 ± 114 ms (p = .06) for recurrence and non-recurrence, respectively. No differences were observed in mean RTT between the two groups. Conclusion VITA enabled quantitative assessment of pro-arrhythmic vulnerability of the substrate which related directly to patient outcomes. The number of induced VTs were the most robust measure of appropriate ICD therapy and post-ablation arrhythmia recurrence. The RTT metrics, related to viable circuit lengths through scar, demonstrated a significant independent association with appropriate ICD therapy. Future studies should investigate the clinical utility of a VITA-guided selection and treatment approach.

Cerebral blood flow changes in schizophrenia patients with auditory verbal hallucinations during low-frequency rTMS treatment.

Auditory verbal hallucinations (AVH) are a prominent symptom of schizophrenia. Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been evidenced to improve the treatment of AVH in schizophrenia. Although abnormalities in resting-state cerebral blood flow (CBF) have been reported in schizophrenia, the perfusion alterations specific to schizophrenia patients with AVH during rTMS require further investigation. In this study, we used arterial spin labeling (ASL) to investigate changes in brain perfusion in schizophrenia patients with AVH, and their associations with clinical improvement following low-frequency rTMS treatment applied to the left temporoparietal junction area. We observed improvements in clinical symptoms (e.g., positive symptoms and AVH) and certain neurocognitive functions (e.g., verbal learning and visual learning) following treatment. Furthermore, at baseline, the patients showed reductions in CBF in regions associated with language, sensory, and cognition compared to controls, primarily located in the prefrontal cortices (e.g., left inferior frontal gyrus and left middle frontal gyrus), occipital lobe (e.g., left calcarine cortex), and cingulate cortex (e.g., bilateral middle cingulate cortex), compared to controls. Conversely, we observed increased CBF in the left inferior temporal gyrus and bilateral putamen in patients relative to controls, regions known to be involved in AVH. However, the hypoperfusion or hyperperfusion patterns did not persist and instead were normalized, and were related to clinical response (e.g., AVH) in patients during low-frequency rTMS treatment. Importantly, the changes in brainperfusion were related to clinical response (e.g., AVH) in patients. Our findings suggest that low-frequency rTMS can regulate brain perfusion involving critical circuits by its remote effect in schizophrenia, and may play an important mechanistic role in the treatment of AVH.

IPD dual-band filter chip with a large frequency ratio for 5G microwave and millimeter-wave applications

In this paper, a dual-band integrated passive device (IPD) filter with an almost arbitrary large frequency ratio is proposed and it has passbands at sub-6GHz and millimeter-wave frequencies. The method to design this kind of filter is summarized. A comprehensive qualitative analysis shows how the coupled lines are used to separate high-frequency (HF) and low-frequency (LF) signals and multiple open stubs as well as LC resonators are involved in this kind of filter. According to the odd- and even-mode analytical methods, the relationship between critical transmission zeros (TZs) and circuit parameters of the dual-band filter is explained. A good selectivity is achieved to suppress intermodulation signals. A prototype of the dual-band filter chip working at 4.80 GHz and 28.29 GHz with 3-dB fractional bandwidths of 53.81% and 24.52% is implemented, indicating that it supports more 5G bands than previous designs and has a good application prospect.

Omnipolar mapping improves substrate characterization and critical isthmus identification in atypical atrial flutters

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Characterizing atrial substrate and conduction properties is crucial to treat complex arrhythmias during catheter ablations. Unipolar and bipolar electrogram signals are routinely used with significant limits due to low detailed mapping, the impact of poor contact and far-field electrical signals. Moreover, signals morphology is dependent on the relative orientation of the catheter inter-electrode axis to the direction of activation. Omnipolar signals try to overcome this direction-dependence by using three adjacent electrodes to infer directional information about the local electric field. Purpose We compared omnipolar mapping (OM) signals with the traditional high-density bipolar mapping (BM) ones. Methods All the procedures were performed using a high-density grid-designed mapping catheter. The atypical left atrial flutters were mapped using both OM and BM configuration. All the analysis about voltage and potential duration are related to the entire left atrial surface excluding pulmonary veins. Results Ten atypical atrial flutters were mapped in the left atrium in seven patients (median age 70 y, 5 males). OM identified 7 double loops and 3 triple loops while BM identified 7 double loops, 2 triple loops and 1 single loop, missing 2 critical circuits (an example is shown in figure 1) Significant differences were present also in potentials amplitude (peak-to-peak voltage amplitude) in the critical isthmus with OM higher than BM (OM median 0.22 mV IQR [0.16 – 0.30] vs BM median 0.19 mV IQR [0.13 – 0.24], P= 0.002). Dense scar area (defined as voltage amplitude <0.05 mV) identified with OM was smaller compared to BM (1.3 cm2 IQR [0.13-1.73] vs 1.7 cm2 IQR [0.23-3.10]; P= 0.06). OM showed longer signal duration (+10.1%) compared to BM in the entire left atrium and in particular the mean signal duration in the critical isthmus (OM median 79.1 ms IQR [70.7 – 88.9] vs BM median 62.5 ms IQR [55.2 – 85.2], P= 0.006). Percentage of tachycardia cycle lenght (TCL) mapped at the critical isthmus (maximum signal duration at the isthmus/ TCL) was greater with OM than BM (OM mean 60% ± 11%, BM mean 54% ± 12% (P= 0.02)(a summary of the results are shown in table 1). Conclusions OM identifies higher amplitude and longer signal duration especially in the critical isthmus region also reducing the extension of dense scar area. This finding may be crucial in the definition of complex and localized reentrant activities, leading to a faster and more precise catheter ablation.

Predicting ICD therapy and post-ablation ventricular tachycardia recurrence using cardiac MRI-based advanced computational reentrant pathway analysis

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Netherlands Heart Institute Fellowship, CVON PREDICT2 Young Talent Program Background MRI late gadolinium enhancement (LGE) images can provide novel insights about critical pathways through scar but does not assess the vulnerability of these pathways for sustaining scar-mediated ventricular tachycardia (VT). Computational modelling can augment the insights from imaging derived metrics by providing the functional implications of structural anatomy of the substrate. However, current (monodomain) approaches are computationally expensive and may not, by design, extract all critical pathways. Aim This study evaluated the performance of a novel, reaction-Eikonal based, automated reentrant pathway finding algorithm (VITA) to assess the functional viability of critical circuits identified on LGE and non-invasively predict arrhythmic risk in both an ICD and post-ablation cohort recurrence. Methods ADAS LV and custom-made software was used to generate 3D patient-specific ventricular models in a prospective cohort of post-infarct ICD patients (cohort 1, n=40) and a retrospective cohort of 20 post-infarct VT-ablation patients (cohort 2). Our Virtual Induction and Treatment of Arrhythmias (VITA) framework was then applied to comprehensively probe the viability of the scar substrate to sustaining reentrant circuits. VITA metrics, related to the numbers of induced VTs and their corresponding round trip times (RTTs), were compared with appropriate ICD therapy (cohort 1) and VT-recurrence (cohort 2) during follow-up. Results Patients in both cohorts with an event had higher VITA metrics. In cohort 1 (ICD), VITA demonstrated significantly more inducible VTs (6.6±4.2 vs. 4.1±3.4, p = .044), longer mean RTT (116.2±50.9 ms vs. 76.9±42.6 ms, p=.012) and max RTT (194.4±105.1 ms vs. 109.6±78.7, p =.009) in the event group. In addition, Cox-regression demonstrated a significant independent association with an event: induced VTs (HR 1.67; CI 1.04–2.68, p = .03), mean RTT (HR 2.14; CI 1.11–4.12, p = .02), maximum RTT (HR 2.13; CI 1.19–3.81, p = .01). In cohort 2 (VT-ablation), total induced VTs (85±43 vs. 42±27, p = .01) and unique VTs (9±4 vs. 5±4, p = .04) were significantly higher in patients with- compared to patients without recurrence, and were predictive of recurrence with AUC of .820 and .770, respectively. Max RTT demonstrated a trend towards significance 293 ± 90 ms vs. 200 ± 114 ms (p = .06) for recurrence and non-recurrence, respectively. No differences were observed in mean RTT between the two groups. Conclusion VITA enabled quantitative assessment of pro-arrhythmic vulnerability of the substrate which related directly to patient outcomes. The number of induced VTs were the most robust measure of appropriate ICD therapy and post-ablation arrhythmia recurrence. The RTT metrics, related to viable circuit lengths through scar, demonstrated a significant independent association with appropriate ICD therapy. Future studies should investigate the clinical utility of a VITA-guided selection and treatment approach.