Background:Regional activation and pairwise correlation are mainstay neuroimaging methods. Yet, neither approach fully captures brain networks' temporal evolution and interaction. The maximum entropy model (MEM), which integrates regional and inter-regional activity, represents a promising integrative approach to examine dynamically evolving functional networks. Methods:Activation-only, pairwise-coactivation-only, and MEM-based analyses were applied to the Human Connectome Project-Early Psychosis dataset (patients=109, controls=56). Using the HCP/Glasser atlas to define brain regions from the default mode (DMN) and dorsal attention (DAN) networks, group differences were quantified in nodal frequency band power, functional connectivity (FC), and MEM features such as transition rates between basins in energy landscapes and their associations with cognitive and psychopathological measures. Results:Psychosis was associated with reduced BOLD frequency band power and FC graph metrics. The MEM demonstrated a variety of DMN and DAN nodal activation/deactivation patterns, with more frequent switching between them during the resting state in psychosis. Higher basin transitions with reduced basin dwell times were observed in DMN and DAN nodes, more prominently in DMN+DAN system. BOLD frequency band power of three regions correlated positively with working memory, but FC graph metrics did not. MEM metrics correlated negatively with working memory and positively with positive symptom severity. Conclusion:The MEM provides unique information unavailable from the other two methods, namely nodal activation/deactivation patterns, basin transitions, and energy. Network-level results were better characterized in the MEM analysis as attenuated inter-network connectivity with reduced stability of DMN and DAN in psychosis that may underlie impaired working memory and psychopathology severity.

Conventional color flow processing is primarily optimized for qualitative visualization of flow dynamics, limiting its diagnostic use in regions where vascular structures are small relative to the ultrasound beamwidth. Leveraging the statistical properties of color flow data may provide a pathway toward quantitative discrimination between blood and tissue signals. This could enhance detection of vascular abnormalities, improve diagnostic accuracy, and support monitoring in diseases with small hemodynamic changes. Experimental data were obtained using a clinical GE LOGIQ 9 ultrasound system with a 10L linear array probe (3.75 MHz) positioned on an in-house made half-space flow phantom with the focus located at 3 cm depth. The simulation data obtained from Field II used a setup analogous to the experimental settings. Theoretical probability density function of ultrasound color flow power was derived using a gamma distribution. Shape parameters for blood and tissue were estimated using maximum likelihood estimation (MLE) in both simulation and experimental data. Color flow power was found to follow the gamma distribution in both simulation and experimental data. The estimated shape parameters aligned with theoretical predictions and distinguished between blood and tissue. Estimated shape parameters are less than or equal to 1 for tissue samples and greater than 1 for blood samples. This study presents a statistical modeling approach to enhance blood-tissue differentiation in color flow ultrasound, enabling blood characterization and perfusion quantification for improved detection and monitoring of vascular abnormalities.

Various mathematical models have been formulated to describe the changes in synaptic strengths resulting from spike-timing-dependent plasticity (STDP). A subset of these models include a third factor, dopamine, which interacts with spike timing to contribute to plasticity at specific synapses, notably those from cortex to striatum at the input layer of the basal ganglia. Theoretical work to analyze these plasticity models has largely focused on abstract issues, such as the conditions under which they may promote synchronization and the weight distributions induced by inputs with simple correlation structures, rather than on scenarios associated with specific tasks, and has generally not considered dopamine-dependent forms of STDP. In this paper we introduce forms of dopamine-modulated STDP adapted from previously proposed plasticity rules. We then analyze, mathematically and with simulations, their performance in two biologically relevant scenarios. We test the ability of each of the three models to complete simple value estimation and action selection tasks, studying the learned weight distributions and corresponding task performance in each setting. Interestingly, we find that each plasticity rule is well suited to a subset of the scenarios studied but falls short in others. Different tasks may therefore require different forms of synaptic plasticity, yielding the prediction that the precise form of the STDP mechanism present may vary across regions of the striatum, and other brain areas impacted by dopamine, that are involved in distinct computational functions.

Recent computational studies of Parkinson's disease have yielded contradictory findings regarding the role of the subthalamic nucleus (STN) in pathological beta oscillations, with some models implicating STN as essential for beta generation and others suggesting that STN suppresses oscillations. This work addresses these discrepancies by systematically investigating how the specific features of the integrate-and-fire neurons used in these models influence simulated basal ganglia network dynamics. Using both rate models and spiking network simulations incorporating coupled subthalamopallidal and pallidostriatal circuits, we demonstrate that the choice between leaky integrate-and-fire (LIF) and quadratic integrate-and-fire (QIF) models to represent STN neurons fundamentally impacts the phase relationship between STN and external globus pallidus prototypical (Proto) neuron populations. QIF STN neurons establish in-phase coupling with Proto neurons, which enhances beta oscillation amplitude, while LIF STN neurons develop anti-phase relationships that suppress beta power. Through intervention experiments and parameter sweeps across physiologically relevant firing rates, we show that these phase-related effects persist robustly across network conditions, and we mathematically establish conditions under which these results are guaranteed to hold. Our findings reveal that the fundamental mathematical structure underlying spike generation, rather than other biophysical details, determines whether the subthalamopallidal loop acts as a beta amplifier or suppressor. This mechanistic insight reconciles contradictory findings in the literature, demonstrates that seemingly minor modeling choices can have profound consequences for understanding disease mechanisms and therapeutic targets, and offers predictions for determining which model framework reflects the biological reality.

Spread of information within a wide variety of systems can be represented as evolving processes on digraphs. Starting from a random subset of initially active vertices, the measures we introduce assess the probability, speed, or number of steps it takes to spread information to the entire digraph, thus achieving digraph synchrony. Some of these measures may be viewed as generalizations of digraph connectivity or as generalizations of the diameter of a digraph to higher-order diameters. The paper places considerable emphasis on the regular case of Cayley digraphs associated to finite groups. It is demonstrated that, with appropriate assumptions on the growth of the generating sets, all the higher-order diameters of random Cayley digraphs are almost surely at most 2, as the digraph order goes to infinity. Certain results on the velocity of spread of information in digraphs are also presented.

All mammals exhibit flexible decision policies that depend, at least in part, on the cortico-basal ganglia-thalamic (CBGT) pathways. Yet understanding how the complex connectivity, dynamics, and plasticity of CBGT circuits translate into experience-dependent shifts of decision policies represents a longstanding challenge in neuroscience. Here we present the results of a computational approach to address this problem. Specifically, we simulated decisions during the early learning process driven by CBGT circuits under baseline, unrewarded conditions using a spiking neural network, and fit an evidence accumulation model to the resulting behavior. Using canonical correlation analysis, we then replicated the identification of three control ensembles (responsiveness, pliancy and choice) within CBGT circuits, with each of these subnetworks mapping to a specific configuration of the evidence accumulation process. We subsequently simulated learning in a simple two-choice task with one optimal (i.e., rewarded) target and found that, during early stages of learning, feedback-driven dopaminergic plasticity on cortico-striatal synapses effectively increases reward rate over time. The learning-related changes in the decision policy can be decomposed in terms of the contributions of each control ensemble, whose influence is driven by sequential reward prediction errors on individual trials. Our results provide a clear and simple mechanism for how dopaminergic plasticity shifts subnetworks within CBGT circuits so as to increase reward rate by strategically modulating how evidence is used to drive decisions.

Here we introduce CBGTPy, a virtual environment for designing and testing goal-directed agents with internal dynamics that are modeled on the cortico-basal-ganglia-thalamic (CBGT) pathways in the mammalian brain. CBGTPy enables researchers to investigate the internal dynamics of the CBGT system during a variety of tasks, allowing for the formation of testable predictions about animal behavior and neural activity. The framework has been designed around the principle of flexibility, such that many experimental parameters in a decision making paradigm can be easily defined and modified. Here we demonstrate the capabilities of CBGTPy across a range of single and multi-choice tasks, highlighting the ease of set up and the biologically realistic behavior that it produces. We show that CBGTPy is extensible enough to apply to a range of experimental protocols and to allow for the implementation of model extensions with minimal developmental effort.

BackgroundUltrasound lung surface motion measurement is valuable for the evaluation of a variety of diseases. Speckle tracking or Doppler-based techniques are limited by the loss of visualization as a tracked point moves under ribs or is dependent.MethodsWe developed a synthetic lateral phase-based algorithm for tracking lung motion to overcome these limitations. To validate the technique, we generated simulated lung motion images. We also obtained lung ultrasound cines from a healthy volunteer and a mechanically ventilated COVID-19 patient. In the healthy volunteer, the respiratory pattern varied between breath-hold, regular, and rapid shallow breathing.ResultsThe measured displacement was within 3% of the ground truth for simulated cines. In both the healthy volunteer and COVID-19 patients, measured displacement was greatest in the lower and lateral zones of the lung when the ipsilateral side was compared. In the healthy volunteer, when the respiratory pattern was varied, measured displacement was greater in regular breathing compared to rapid shallow breathing and compared to breath-hold patterns in both the upper and lower lung zones.ConclusionEstimation of lung surface displacement using a synthetic lateral phase-based approach is feasible. Future human studies should validate this approach against a direct measurement of lung surface movement.

Objectives To discuss challenges in assessing hepatic steatosis using ultrasound hepatorenal index (HRI). Methods We retrospectively analyzed HRI and liver magnetic resonance imaging‐based proton density fat fraction (MRI‐PDFF) in 134 adult participants (53 men and 81 women, mean age 55 years). The diagnostic performance of HRI for determining hepatic steatosis was tested by the area under the receiver operating characteristic curve (AUROC) using liver MRI‐PDFF as the reference. Regression plots were employed to compare the sampling sites in liver and kidney that were used to calculate HRIs. Results In 11 of 134 cases (8.2%), we failed to acquire HRI measurements. In the remaining 123 cases, AUROC for HRI (cutoff: 1.69 ± 0.13 [mean ± standard deviation]) for defining the HRI threshold for diagnosing hepatic steatosis was 0.83. In 60 of 123 cases (49%) with HRI measurement IQR/median >0.3, slopes of the regression lines in the liver showed backscatter intensity changes consistent with signal attenuation. However, in the kidney, the backscatter intensity was inverted yielding position‐dependent HRI cutoff values, mid‐pole = 2.24 ± 0.20 and upper pole = 1.08 ± 0.16. Conclusions HRI is used to estimate liver steatosis based on backscattered ultrasound. In order to compensate for effects such as body habitus and transducer frequency, the liver backscatter is divided by backscatter from a corresponding region at the same depth in the right renal cortex. Theoretically, this compensation should make HRI sampling position independent. Yet, due to renal cortical backscatter anisotropy, this compensation method does not work in general, potentially producing inaccurate liver fat estimates.

Several inhibitory interneuron subtypes have been identified as critical in regulating sensory responses. However, the specific contribution of each interneuron subtype remains uncertain. In this work, we explore the contributions of cell type-specific activity and synaptic connections to the dynamics of a spatially organized spiking neuron network. We find that the firing rates of the somatostatin (SOM) interneurons align closely with the level of network synchrony irrespective of the target of modulatory input. Further analysis reveals that inhibition from SOM to parvalbumin interneurons must be limited to allow gradual transitions from asynchrony to synchrony and that the strength of recurrent excitation onto SOM neurons determines the level of synchrony achievable in the network. Our results are consistent with recent experimental findings on cell type-specific manipulations. Overall, our results highlight common dynamic regimes achieved across modulations of different cell populations and identify SOM cells as the main driver of network synchrony.

Introduction: Viloxazine extended-release (VLX-ER) is effective as monotherapy for attention-deficit/hyperactivity disorder (ADHD), and is often tried as an add-on treatment when psychostimulant therapy fails to provide an adequate treatment response. This phase 4, open-label study evaluated safety, tolerability, and efficacy of VLX-ER with optimized psychostimulants in pediatric participants with ADHD. Morning versus evening VLX-ER use was also evaluated. Methods: Children and adolescents (6-17 years) experiencing inadequate psychostimulant response (investigator-assessed ADHD Rating Scale-5 [ADHD-RS-5] score ≥24 and Clinical Global Impression-Severity of Illness [CGI-S] scores ≥3) during a 4-week screening period received flexibly-dosed VLX-ER, taken once daily in the morning (weeks 14) or evening (weeks 5-8), concomitantly with a psychostimulant. Safety (primary outcome) and efficacy were evaluated relative to baseline. Results: Fifty-six participants (26 children; 30 adolescents) enrolled, and 48 (85.7%) completed the study. Combination therapy was well tolerated, with only two participants (3.6%) withdrawing due to adverse events (AEs). The most commonly reported AEs were headache (17.9%), decreased appetite (12.5%), and upper respiratory tract infection (10.7%). Mean ± standard deviation investigator-assessed ADHD-RS-5 scores (baseline: 37.2 ± 8.4) improved progressively by -13.5 ± 9.7 points at week 4 and -18.2 ± 10.0 points at week 8 (p < 0.0001 each). Likewise, CGI-S scores (baseline: 4.4 ± 0.6) improved by -0.9 ± 0.9 at week 4 and -1.4 ± 1.1 at week 8 (p < 0.0001 each). Parent-assessed scales, including ratings of morning and evening ADHD behaviors and sleep disturbances, showed significant improvement relative to baseline regardless of morning (week 4) or evening (week 8) VLX-ER dosing. Conclusion: Combined treatment with VLX-ER and psychostimulant therapy showed acceptable safety and tolerability, with improvement in morning and evening ADHD behaviors and sleep disturbances relative to stimulant monotherapy. Timing of VLX-ER administration (morning or evening) did not appear to affect safety, drug response, or sleep improvement.

Adolescent-onset schizophrenia (AOS) is relatively rare, under-studied, and associated with more severe cognitive impairments and poorer outcomes than adult-onset schizophrenia. Neuroimaging has shown altered regional activations (first-order effects) and functional connectivity (second-order effects) in AOS compared to controls. The pairwise maximum entropy model (MEM) integrates first- and second-order factors into a single quantity called energy, which is inversely related to probability of occurrence of brain activity patterns. We take a combinatorial approach to study multiple brain-wide MEMs of task-associated components; hundreds of independent MEMs for various sub-systems were fit to 7 Tesla functional MRI scans. Acquisitions were collected from 23 AOS individuals and 53 healthy controls while performing the Penn Conditional Exclusion Test (PCET) for executive function, which is known to be impaired in AOS. Accuracy of PCET performance was significantly reduced among AOS compared with controls. A majority of the models showed significant negative correlation between PCET scores and the total energy attained over the fMRI. Severity of psychopathology was correlated positively with energy. Across all instantiations, the AOS group was associated with significantly more frequent occurrence of states of higher energy, assessed with a mixed effects model. An example MEM instance was investigated further using energy landscapes, which visualize high and low energy states on a low-dimensional plane, and trajectory analysis, which quantify the evolution of brain states throughout this landscape. Both supported patient-control differences in the energy profiles. The MEM's integrated representation of energy in task-associated systems can help characterize pathophysiology of AOS, cognitive impairments, and psychopathology.

IntroductionViloxazine extended-release (ER) is an FDA-approved nonstimulant medication for ADHD in children (≥6 years) and adults. Approval in adults was based on a double-blind (DB) pivotal trial [NCT04016779] showing statistically significant efficacy on the Adult ADHD Investigator Symptom Rating Scale (AISRS; primary outcome). Here we report final results from the long-term, open-label extension (OLE) safety trial [NCT04143217] conducted as a following to the DB trial.MethodsUpon completing DB treatment, consenting subjects who enrolled in the OLE received viloxazine ER 200 mg/day, with flexible titration to an optimal maintenance dose (200-600 mg/day). Addition of a stimulant was permitted, at investigator’s discretion, following Week 12. OLE trial enrollment was temporarily closed at the outset of the COVID pandemic. Subjects completing the DB during this time were allowed delayed entry into the OLE upon requalification. Safety and efficacy measures were assessed relative to DB (or OLE re-entry) Baseline) at OLE Weeks 2, 4, and ~ every 8 weeks thereafter. The trial was planned for 3 years or until commercial availability of viloxazine ER.ResultsSubjects (N= 159; including 133 immediate- and 26 delayed-rollover) received viloxazine ER for 265 ± 254.9 days (mean ± SD). Nine subjects used adjunctive stimulant medication at some point after Week 12. Primary reasons for discontinuation included withdrawal of consent (25.6%), loss to follow up (17.7%), and adverse events (17.6%). Adverse events (experienced by 72.3%) were largely mild (26.4%) or moderate (40.3%) in severity and included (≥10%) insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). Changes in clinical laboratory measures, vital signs, and ECG parameters were consistent with those observed in DB and product labeling. Suicidal ideation (wish to be dead) was reported by 3 subjects at a single visit each; no subject reported suicidal behavior. ADHD symptom (AISRS), executive function (BRIEF-A), global function (CGI), and quality of life (AAQOL) measures showed continued improvement in the OLE relative to that seen in DB. Baseline [mean ± SD)] AISRS Total, CGI-S, BRIEF-A GEC T-score and AAQOL ratings, respectively, were 37.9 ± 6.34), 4.6 ± 0.60, 70.4 ± 10.94 and 54.9 ± 14.96. All showed significant improvement (P<.0001 relative to Baseline) by the first OLE follow-up assessment (Week 2 for AISRS and CGI-S, Week 4 for BRIEF-A and AAQOL). Improvement continued with long-term use. Subjects maintained on viloxazine ER for at least 3 months (≥ Week 12) showed changes at Last OLE Visit of -20.0 ± 11.63 (n=106), -1.8 ± 1.34, -13.6 ± 13.64 (n=104), and 12.7 ± 17.90 (n=87) respectively.ConclusionsSubjects maintained on viloxazine ER showed continued improvement in ADHD symptoms, global and executive function, and quality of life measures during long-term treatment.FundingSupernus Pharmaceuticals, Inc.

BackgroundBlood flow to the brain is a critical physiological function and is useful to monitor in critical care settings. Despite that, a surrogate is most likely measured instead of actual blood flow. Such surrogates include velocity measurements in the carotid artery and systemic blood pressure, even though true blood flow can actually be obtained using MRI and other modalities. Ultrasound is regularly used to measure blood flow and is, under certain conditions, able to provide quantitative volumetric blood flow in milliliters per minute. Unfortunately, most times the resulting flow data is not valid due to unmet assumptions (such as flow profile and angle correction). Color flow, acquired in three dimensions, has been shown to yield quantitative blood flow without any assumptions (3DVF).MethodsHere we are testing whether color flow can perform during physiological conditions common to severe injury. Specifically, we are simulating severe traumatic brain injury (epidural hematoma) as well as hemorrhagic shock with 50% blood loss. Blood flow was measured in the carotid artery of a cohort of 7 Yorkshire mix pigs (40–60 kg) using 3DVF (4D16L, LOGIQ 9, GE HealthCare, Milwaukee, WI, USA) and compared to an invasive flow meter (TS420, Transonic Systems Inc., Ithaca, NY, USA).ResultsSix distinct physiological conditions were achieved: baseline, hematoma, baseline 2, hemorrhagic shock, hemorrhagic shock plus hematoma, and post-hemorrhage resuscitation. Mean cerebral oxygen extraction ratio varied from 40.6% ± 13.0% of baseline to a peak of 68.4% ± 15.6% during hemorrhagic shock. On average 3DVF estimated blood flow with a bias of -9.6% (-14.3% root mean squared error) relative to the invasive flow meter. No significant flow estimation error was detected during phases of flow reversal, that was seen in the carotid artery during traumatic conditions. The invasive flow meter showed a median error of -11.5% to 39.7%.ConclusionsResults suggest that absolute volumetric carotid blood flow to the brain can be obtained and potentially become a more specific biomarker related to cerebral hemodynamics than current surrogate markers.

Background:Viloxazine ER (viloxazine extended-release capsules; Qelbree®), a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment, has known activity as a norepinephrine (NE) transporter (NET) inhibitor. In vitro studies have also shown direct pharmacological effects on specific serotonin (5-HT) receptors, but not on the serotonin transporter (SERT). An in vivo microdialysis study in rats showed viloxazine (50 mg/kg i.p.) increased extracellular 5-HT, NE, and dopamine (DA) in the prefrontal cortex (PFC), a key brain region in ADHD pathology. This study evaluated whether these effects occur at clinically relevant concentrations.Methods:Microdialysis experiments were conducted in freely-moving, Sprague-Dawley rats (males, 8 weeks). Viloxazine (1, 3, 10, 30 mg/kg) was administered intraperitoneally to establish the dose range in rats at which viloxazine plasma concentrations aligned with those of individuals with ADHD administered therapeutic doses of viloxazine ER. Concentrations of unbound viloxazine, NE, 5-HT, DA, and NE and 5-HT metabolites (3,5-dihydroxyphenylglycol [DHPG] and 5-hydroxyindoleacetic acid [5-HIAA]) were measured in PFC interstitial fluid. After identifying a therapeutically relevant dose (30 mg/kg), the experiment was repeated using 30 and 50 mg/kg viloxazine (as 50 mg/kg increased NE, 5-HT, and DA in prior studies).Results:Viloxazine unbound (free drug) plasma concentrations in rats at 30 mg/kg were comparable to free drug concentrations in individuals with ADHD taking clinically effective doses (based on validated population PK models). Viloxazine 30 mg/kg significantly increased extracellular NE, 5-HT, and DA PFC levels compared to vehicle. Concomitant decreases in DHPG, but not 5-HIAA, support the inhibitory effect of viloxazine on NET but not SERT.Conclusion:At clinically relevant concentrations, viloxazine increases PFC NE, DA, and 5-HT. Prefrontal augmentation of 5-HT does not appear to result from 5-HT reuptake inhibition but may be related to activation of 5-HT neurons. The potential therapeutic role of serotonergic effects in ADHD treatment merits further exploration.

Neurons in the substantia nigra reticulata (SNr) transmit information about basal ganglia output to dozens of brain regions in thalamocortical and brainstem motor networks. Activity of SNr neurons is regulated by convergent input from upstream basal ganglia nuclei, including GABAergic inputs from the striatum and the external globus pallidus (GPe). GABAergic inputs from the striatum convey information from the direct pathway, while GABAergic inputs from the GPe convey information from the indirect pathway. Chronic loss of dopamine, as occurs in Parkinson's disease, disrupts the balance of direct and indirect pathway neurons at the level of the striatum, but the question of how dopamine loss affects information propagation along these pathways outside of the striatum is less well understood. Using a combination of in vivo and slice electrophysiology, we find that dopamine depletion selectively weakens the direct pathway's influence over neural activity in the SNr due to changes in the decay kinetics of GABA-mediated synaptic currents. GABAergic signaling from GPe neurons in the indirect pathway was not affected, resulting in an inversion of the normal balance of inhibitory control over basal ganglia output through the SNr. These results highlight the contribution of cellular mechanisms outside of the striatum that impact the responses of basal ganglia output neurons to the direct and indirect pathways in disease.

ObjectiveThe purpose of this study was to quantify the accuracy of partial volume-corrected three-dimensional volume flow (3DVF) measurements as a function of spatial sampling beam density using carefully-designed parametric analyses in order to inform the target applications of 3DVF.MethodsExperimental investigations employed a mechanically-swept curvilinear ultrasound array to acquire 3D color flow (6.3 MHz) images in flow phantoms consisting of four lumen diameters (6.35, 4.88, 3.18 and 1.65 mm) with volume flow rates of 440, 260, 110 and 30 mL/min, respectively. Partial volume-corrected three-dimensional volume flow (3DVF) measurements, based on the Gaussian surface integration principle, were computed at five regions of interest positioned between depths of 2 and 6 cm in 1 cm increments. At each depth, the color flow beam point spread function (PSF) was also determined, using in-phase/quadrature data, such that 3DVF bias could then be related to spatial sampling beam density. Corresponding simulations were performed for a laminar parabolic flow profile that was sampled using the experimentally-measured PSFs. Volume flow was computed for all combinations of lumen diameters and the PSFs at each depth.ResultsAccurate 3DVF measurements, i.e., bias less than ±20%, were achieved for spatial sampling beam densities where at least 6 elevational color flow beams could be positioned across the lumen. In these cases, greater than 8 lateral color flow beams were present. PSF measurements showed an average lateral-to-elevational beam width asymmetry of 1:2. Volume flow measurement bias increased as the color flow beam spatial sampling density within the lumen decreased.ConclusionApplications of 3DVF, particularly those in the clinical domain, should focus on areas where a spatial sampling density of 6 × 6 (lateral x elevational) beams can be realized in order to minimize measurement bias. Matrix-based ultrasound arrays that possess symmetric PSFs may be advantageous to achieve adequate beam densities in smaller vessels.