Optical coherence tomography-based design for a real-time motion corrected scanning microscope.

While two-photon fluorescence microscopy is a powerful platform for the study of functional dynamics in living cells and tissues, the bulk motion inherent to these applications causes distortions. We have designed a motion tracking module based on spectral domain optical coherence tomography which compliments a laser scanning two-photon microscope with real-time corrective feedback. The module can be added to fluorescent imaging microscopes using a single dichroic and without additional contrast agents. We demonstrate that the system can track lateral displacements as large as 10 µm at 5 Hz with latency under 14 ms and propose a scheme to extend the system to 3D correction with the addition of a remote focusing module. We also propose several ways to improve the module's performance by reducing the feedback latency. We anticipate that this design can be adapted to other imaging modalities, enabling the study of samples subject to motion artifacts at higher resolution.

Constraining Axion Inflation with Gravitational Waves across 29 Decades in Frequency.

We demonstrate that gravitational waves generated by efficient gauge preheating after axion inflation generically contribute significantly to the effective number of relativistic degrees of freedom N_{eff}. We show that, with existing Planck limits, gravitational waves from preheating already place the strongest constraints on the inflaton's possible axial coupling to Abelian gauge fields. We demonstrate that gauge preheating can completely reheat the Universe regardless of the inflationary potential. Further, we quantify the variation of the efficiency of gravitational wave production from model to model and show that it is correlated with the tensor-to-scalar ratio. In particular, when combined with constraints on models whose tensor-to-scalar ratios would be detected by next-generation cosmic microwave background experiments, r≳10^{-3}, constraints from N_{eff} will probe or rule out the entire coupling regime for which gauge preheating is efficient.

Nonlinear Dynamics of Preheating after Multifield Inflation with Nonminimal Couplings.

We study the postinflation dynamics of multifield models involving nonminimal couplings using lattice simulations to capture significant nonlinear effects like backreaction and rescattering. We measure the effective equation of state and typical timescales for the onset of thermalization, which could affect the usual mapping between predictions for primordial perturbation spectra and measurements of anisotropies in the cosmic microwave background radiation. For large values of the nonminimal coupling constants, we find efficient particle production that gives rise to nearly instantaneous preheating. Moreover, the strong single-field attractor behavior that was previously identified persists until the end of preheating, thereby suppressing typical signatures of multifield models. We therefore find that predictions for primordial observables in this class of models retain a close match to the latest observations.

Departures from the Friedmann-Lemaitre-Robertston-Walker Cosmological Model in an Inhomogeneous Universe: A Numerical Examination.

While the use of numerical general relativity for modeling astrophysical phenomena and compact objects is commonplace, the application to cosmological scenarios is only just beginning. Here, we examine the expansion of a spacetime using the Baumgarte-Shapiro-Shibata-Nakamura formalism of numerical relativity in synchronous gauge. This work represents the first numerical cosmological study that is fully relativistic, nonlinear, and without symmetry. The universe that emerges exhibits an average Friedmann-Lemaître-Robertson-Walker (FLRW) behavior; however, this universe also exhibits locally inhomogeneous expansion beyond that expected in linear perturbation theory around a FLRW background.

Preheating with nonminimal kinetic terms.

We present the first (3+1)-dimensional numerical simulations of scalar fields with nonminimal kinetic terms. As an example, we examine the existence and stability of preheating in the presence of a Dirac-Born-Infeld inflaton coupled to a canonical matter field. The simulations represent the full nonlinear theory in the presence of an expanding universe. We show that parametric resonance in the matter field along with self-resonance in the inflaton repopulate the universe with matter particles as efficiently as in traditional preheating.

High-throughput deep tissue two-photon microscopy at kilohertz frame rates.

High-speed laser scanning microscopes are essential for monitoring fast biological phenomena. However, existing strategies that achieve millisecond time resolution with two-photon microscopes (2PMs) are generally technically challenging and suffer from compromises among imaging field of view, excitation efficiency, and depth penetration in thick tissue. Here, we present a versatile solution that enables a conventional video-rate 2PM to perform 2D scanning at kilohertz frame rates over large fields of view. Our system is based on implementation of a scan multiplier unit that provides inertia-free multiplication of the scanning speed while preserving all the benefits of standard 2PM. We demonstrate kilohertz subcellular-resolution 2PM imaging with an order of magnitude higher imaging throughput than previously achievable and penetration depths exceeding 500 µm, which we apply to the study of neurovascular coupling dynamics in the mouse brain.

Measuring capillary flow dynamics using interlaced two-photon volumetric scanning.

Two photon microscopy and optical coherence tomography (OCT) are two standard methods for measuring flow speeds of red blood cells in microvessels, particularly in animal models. However, traditional two photon microscopy lacks the depth of field to adequately capture the full volumetric complexity of the cerebral microvasculature and OCT lacks the specificity offered by fluorescent labeling. In addition, the traditional raster scanning technique utilized in both modalities requires a balance of image frame rate and field of view, which severely limits the study of RBC velocities in the microvascular network. Here, we overcome this by using a custom two photon system with an axicon based Bessel beam to obtain volumetric images of the microvascular network with fluorescent specificity. We combine this with a novel scan pattern that generates pairs of frames with short time delay sufficient for tracking red blood cell flow in capillaries. We track RBC flow speeds in 10 or more capillaries simultaneously at 1 Hz in a 237 µm × 237 µm × 120 µm volume and quantified both their spatial and temporal variability in speed. We also demonstrate the ability to track flow speed changes around stalls in capillary flow and measure to 300 µm in depth.

Neurovascular Uncoupling Is Linked to Microcirculatory Dysfunction in Regions Outside the Ischemic Core Following Ischemic Stroke.

Background Normal brain function depends on the ability of the vasculature to increase blood flow to regions with high metabolic demands. Impaired neurovascular coupling, such as the local hyperemic response to neuronal activity, may contribute to poor neurological outcome after stroke despite successful recanalization, that is, futile recanalization. Methods and Results Mice implanted with chronic cranial windows were trained for awake head-fixation before experiments. One-hour occlusion of the anterior middle cerebral artery branch was induced using single-vessel photothrombosis. Cerebral perfusion and neurovascular coupling were assessed by optical coherence tomography and laser speckle contrast imaging. Capillaries and pericytes were studied in perfusion-fixed tissue by labeling lectin and platelet-derived growth factor receptor ß. Arterial occlusion induced multiple spreading depolarizations over 1 hour associated with substantially reduced blood flow in the peri-ischemic cortex. Approximately half of the capillaries in the peri-ischemic area were no longer perfused at the 3- and 24-hour follow-up (45% [95% CI, 33%-58%] and 53% [95% CI, 39%-66%] reduction, respectively; P<0.0001), which was associated with contraction of an equivalent proportion of peri-ischemic capillary pericytes. The capillaries in the peri-ischemic cortex that remained perfused showed increased point prevalence of dynamic flow stalling (0.5% [95% CI, 0.2%-0.7%] at baseline, 5.1% [95% CI, 3.2%-6.5%] and 3.2% [95% CI, 1.1%-5.3%] at 3- and 24-hour follow-up, respectively; P=0.001). Whisker stimulation at the 3- and 24-hour follow-up led to reduced neurovascular coupling responses in the sensory cortex corresponding to the peri-ischemic region compared with that observed at baseline. Conclusions Arterial occlusion led to contraction of capillary pericytes and capillary flow stalling in the peri-ischemic cortex. Capillary dysfunction was associated with neurovascular uncoupling. Neurovascular coupling impairment associated with capillary dysfunction may be a mechanism that contributes to futile recanalization. Hence, the results from this study suggest a novel treatment target to improve neurological outcome after stroke.

High throughput detection of capillary stalling events with Bessel beam two-photon microscopy.

Significance: Brief disruptions in capillary flow, commonly referred to as capillary "stalling," have gained interest recently for their potential role in disrupting cerebral blood flow and oxygen delivery. Approaches to studying this phenomenon have been hindered by limited volumetric imaging rates and cumbersome manual analysis. The ability to precisely and efficiently quantify the dynamics of these events will be key in understanding their potential role in stroke and neurodegenerative diseases, such as Alzheimer's disease. Aim: Our study aimed to demonstrate that the fast volumetric imaging rates offered by Bessel beam two-photon microscopy combined with improved data analysis throughput allows for faster and more precise measurement of capillary stall dynamics. Results: We found that while our analysis approach was unable to achieve full automation, we were able to cut analysis time in half while also finding stalling events that were missed in traditional blind manual analysis. The resulting data showed that our Bessel beam system was captured more stalling events compared to optical coherence tomography, particularly shorter stalling events. We then compare differences in stall dynamics between a young and old group of mice as well as a demonstrate changes in stalling before and after photothrombotic model of stroke. Finally, we also demonstrate the ability to monitor arteriole dynamics alongside stall dynamics. Conclusions: Bessel beam two-photon microscopy combined with high throughput analysis is a powerful tool for studying capillary stalling due to its ability to monitor hundreds of capillaries simultaneously at high frame rates.

A randomized, double-blind study of 30 versus 20 mg dexmethylphenidate extended-release in children with attention-deficit/hyperactivity disorder: late-day symptom control.

The objective of this study was to evaluate the safety and efficacy of dexmethylphenidate extended-release (d-MPH-ER) 30 versus 20 mg in children with attention-deficit/hyperactivity disorder (ADHD) in a 12-hour laboratory classroom setting. In a randomized, double-blind, 3-period × 3-treatment, crossover study, children aged 6 to 12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-diagnosed ADHD previously stabilized on MPH (40-60 mg/d) or D-MPH (20-30 mg/day) [corrected] were randomized to receive D-MPH-ER 20 mg/day, 30 mg/day, [corrected] or placebo for 7 days each. Primary efficacy measurements were change in the average SKAMP-Combined [corrected] score from predose to 10, 11, and 12 hours postdose [Avg(10-12)] between 30 mg [corrected] and 20 mg D-MPH-ER. Safety was assessed by adverse events, (AEs), [corrected] vital sign monitoring, and ECGs. [corrected] A total of 165 children were randomized, and 162 included in the intent-to-treat analysis. Mean Avg (10-12) change from pre-dose [corrected] in SKAMP-Combined score was significantly greater for D-MPH-ER 30 mg (-4.47) compared with D-MPH-ER 20 mg (-2.02; P = 0.002). Most common adverse events (≥ 3% in any group) were decreased appetite (6.1%, 4.9%, and 0%), headache (4.3%, 4.3%, and 1.9%), abdominal pain (3.7%, 3.1%, and 3.1%), and tachycardia (1.2%, 3.1%, and 0.6%) for D-MPH-ER 30 mg, D-MPH-ER 20 mg, and placebo, respectively). Significantly greater improvement in ADHD symptoms was noted with D-MPH-ER 30 mg compared with D-MPH-ER 20 mg at hours 10 through 12. Tolerability was comparable between doses. Dexmethylphenidate extended-release 30-mg dose may provide further benefit to patients who do not maintain optimal symptom control later in the day with D-MPH-ER 20 mg.

Dynamic capillary stalls in reperfused ischemic penumbra contribute to injury: A hyperacute role for neutrophils in persistent traffic jams.

Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2-24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.

Randomized, double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design.

BACKGROUND: Duration of efficacy and safety of lisdexamfetamine dimesylate (LDX) was assessed in adults (18-55 years) with attention-deficit/hyperactivity disorder (ADHD) using the simulated adult workplace environment. METHODS: After open-label dose optimization (4-week) with LDX, 30-70 mg/d, subjects entered a 2-week randomized, double-blind, placebo-controlled crossover phase. Efficacy assessments included the Permanent Product Measure of Performance (PERMP) total score (attempted+correct) measured predose and from 2 to 14 hours postdose, averaged across postdose sessions (primary) and at each time point vs placebo (secondary), and ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts at baseline and crossover visits. Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms. RESULTS: Of 127 randomized subjects, 105 were in the intention-to-treat population and 103 completed the study. While receiving LDX vs placebo, adults had greater improvement (P < .0001) in average PERMP total scores as measured by difference in least squares (LS) mean (95% CI): 23.4 (15.6, 31.2). Absolute (P or=10%) during dose optimization were decreased appetite, dry mouth, headache, and insomnia; no TEAEs >or=5% were reported during crossover phase for adults receiving LDX. CONCLUSIONS: LDX significantly improved PERMP scores vs placebo and maintained improvement throughout the day from the first (2 hours) to last (14 hours) postdose time point vs placebo in adults with ADHD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00697515. Safety and Efficacy Workplace Environment Study of Lisdexamfetamine Dimesylate (LDX) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD) http://www.clinicaltrials.gov/ct2/show/NCT00697515?term=NCT00697515&rank=1.

Functional Ultrasound Speckle Decorrelation-Based Velocimetry of the Brain.

A high-speed, contrast-free, quantitative ultrasound velocimetry (vUS) for blood flow velocity imaging throughout the rodent brain is developed based on the normalized first-order temporal autocorrelation function of the ultrasound field signal. vUS is able to quantify blood flow velocity in both transverse and axial directions, and is validated with numerical simulation, phantom experiments, and in vivo measurements. The functional imaging ability of vUS is demonstrated by monitoring the blood flow velocity changes during whisker stimulation in awake mice. Compared to existing Power-Doppler- and Color-Doppler-based functional ultrasound imaging techniques, vUS shows quantitative accuracy in estimating both axial and transverse flow speeds and resistance to acoustic attenuation and high-frequency noise.

Chronic Imaging of Mouse Brain: From Optical Systems to Functional Ultrasound.

Utilization of functional ultrasound (fUS) in cerebral vascular imaging is gaining popularity among neuroscientists. In this article, we describe a chronic surgical preparation method that allows longitudinal studies and therefore is applicable to a wide range of studies, especially on aging, stroke, and neurodegenerative diseases. This method can also be used with awake mice; hence, the deleterious effects of anesthesia on neurovascular responses can be avoided. In addition to fUS imaging, this surgical preparation allows researchers to take advantage of common optical imaging methods to acquire complementary datasets to help increase the technical rigor of studies. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Surgical preparation of mouse chronic cranial windows using polymethylpentene Basic Protocol 2: Imaging of mice with chronic cranial windows.

Epithelial layer unjamming shifts energy metabolism toward glycolysis.

In development of an embryo, healing of a wound, or progression of a carcinoma, a requisite event is collective epithelial cellular migration. For example, cells at the advancing front of a wound edge tend to migrate collectively, elongate substantially, and exert tractions more forcefully compared with cells many ranks behind. With regards to energy metabolism, striking spatial gradients have recently been reported in the wounded epithelium, as well as in the tumor, but within the wounded cell layer little is known about the link between mechanical events and underlying energy metabolism. Using the advancing confluent monolayer of MDCKII cells as a model system, here we report at single cell resolution the evolving spatiotemporal fields of cell migration speeds, cell shapes, and traction forces measured simultaneously with fields of multiple indices of cellular energy metabolism. Compared with the epithelial layer that is unwounded, which is non-migratory, solid-like and jammed, the leading edge of the advancing cell layer is shown to become progressively more migratory, fluid-like, and unjammed. In doing so the cytoplasmic redox ratio becomes progressively smaller, the NADH lifetime becomes progressively shorter, and the mitochondrial membrane potential and glucose uptake become progressively larger. These observations indicate that a metabolic shift toward glycolysis accompanies collective cellular migration but show, further, that this shift occurs throughout the cell layer, even in regions where associated changes in cell shapes, traction forces, and migration velocities have yet to penetrate. In characterizing the wound healing process these morphological, mechanical, and metabolic observations, taken on a cell-by-cell basis, comprise the most comprehensive set of biophysical data yet reported. Together, these data suggest the novel hypothesis that the unjammed phase evolved to accommodate fluid-like migratory dynamics during episodes of tissue wound healing, development, and plasticity, but is more energetically expensive compared with the jammed phase, which evolved to maintain a solid-like non-migratory state that is more energetically economical.

Reverse-Correlation Analysis of the Mechanosensation Circuit and Behavior in C. elegans Reveals Temporal and Spatial Encoding.

Animals must integrate the activity of multiple mechanoreceptors to navigate complex environments. In Caenorhabditis elegans, the general roles of the mechanosensory neurons have been defined, but most studies involve end-point or single-time-point measurements, and thus lack dynamic information. Here, we formulate a set of unbiased quantitative characterizations of the mechanosensory system by using reverse correlation analysis on behavior. We use a custom tracking, selective illumination, and optogenetics platform to compare two mechanosensory systems: the gentle-touch (TRNs) and harsh-touch (PVD) circuits. This method yields characteristic linear filters that allow for the prediction of behavioral responses. The resulting filters are consistent with previous findings and further provide new insights on the dynamics and spatial encoding of the systems. Our results suggest that the tiled network of the gentle-touch neurons has better resolution for spatial encoding than the harsh-touch neurons. Additionally, linear-nonlinear models can predict behavioral responses based only on sensory neuron activity. Our results capture the overall dynamics of behavior induced by the activation of sensory neurons, providing simple transformations that quantitatively characterize these systems. Furthermore, this platform can be extended to capture the behavioral dynamics induced by any neuron or other excitable cells in the animal.

A randomized, double-blind, crossover study of once-daily dexmethylphenidate in children with attention-deficit hyperactivity disorder: rapid onset of effect.

BACKGROUND: Long-acting methylphenidate formulations provide control of attention-deficit hyperactivity disorder (ADHD) symptoms for up to 12 hours; however, not all formulations have rapid onset of therapeutic effect, which is essential for providing symptom control during morning hours. The primary objective of this randomized, double-blind, crossover study was to assess the efficacy of dexmethylphenidate extended release (ER) versus placebo by measuring the change from pre-dose to 0.5 hours post-dose on the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) rating scale. METHODS: Eighty-six children (6-12 years) with ADHD diagnosed using the DSM-IV criteria were randomized to receive dexmethylphenidate ER 20 mg/day or placebo, sequentially, for 7 days, with the final dose administered in a laboratory classroom setting on day 7 of each treatment period. The primary efficacy comparison was change in the SKAMP-Combined score from pre-dose to 0.5 hours post-dose, with additional secondary assessments at 1, 2, 4, 6 and 8 hours post-dose. Secondary efficacy measures included change from pre-dose at all timepoints in the SKAMP-Attention and SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores, and change from baseline on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P). In an exploratory analysis, a daily diary card was completed by parents on the children's in-home behaviour before school. Safety was assessed by occurrence of adverse events, monitoring of vital signs and interpretation of ECGs. RESULTS: Significant improvements were noted at 0.5 hours and at all timepoints post-dose throughout the 8-hour laboratory classroom day for dexmethylphenidate ER vs placebo in the primary outcome measure of the SKAMP-Combined scores (p < 0.001), as well as SKAMP-Attention, SKAMP-Deportment, Math Test-Attempted and Math Test-Correct scores (p < 0.05). The changes from baseline in CADS-P scores were significantly greater with dexmethylphenidate ER than placebo (-16.382 vs -4.622; p < 0.001). Responses to all diary questions indicated significant improvement with dexmethylphenidate ER treatment versus placebo (all p < 0.001). The most common adverse events were abdominal pain (dexmethylphenidate ER 3.5%; placebo 4.7%), headache (dexmethylphenidate ER 3.5%; placebo 2.3%) and increased appetite (dexmethylphenidate ER 0%; placebo 3.5%). CONCLUSION: Compared with placebo, once-daily dexmethylphenidate ER 20 mg provided rapid and significant improvement at 0.5 hours post-dose in attention, deportment and academic performance, which was sustained for 8 hours post-dose. Overall, once-daily dexmethylphenidate ER 20 mg was well tolerated. In an analysis of parental assessment of diary responses, children appeared more organized, and morning preparation for school was smoother and less frustrating with once-daily dexmethylphenidate ER compared with placebo.

Effect of lisdexamfetamine dimesylate on sleep in children with ADHD.

OBJECTIVE: This study evaluated the potential effects of short-term treatment with lisdexamfetamine dimesylate (LDX) on both subjective and objective sleep characteristics in children aged 6 to 12 years (n = 24) with ADHD. METHOD: Polysomnography (PSG) and actigraph measures as well as assessments of subjective sleep parameters were examined in children before and after treatment with either LDX or placebo in a randomized, double-blind, single-center, parallel-group study. RESULTS: There was no statistically significant increase in the primary endpoint of latency to persistent sleep (LPS) for the LDX-treated group compared to the placebo group. Secondary PSG or actigraph results generally supported primary endpoint results. Subjective sleep measure results indicated the possibility that responses are influenced by sleep hygiene counseling before and throughout the study. CONCLUSIONS: In this pilot sleep study in children with ADHD, LDX did not appear to contribute to any sleep disturbances as measured by both objective and subjective sleep parameters. The sample used in this study was small, and the multifarious nature of findings in this study warranted that the study conclusions be interpreted cautiously and that further study is required focusing on the influence of LDX on sleep in larger samples of ADHD children.

Effects of open-label lisdexamfetamine dimesylate on self-reported quality of life in adults with ADHD.

OBJECTIVE: To assess improvements in quality of life measurements during the open-label portion of a trial examining duration of efficacy of lisdexamfetamine dimesylate in a simulated adult workplace environment. METHODS: A 4-week, open-label, dose-optimization phase followed by a randomized, double-blind, multicenter, placebo-controlled, 2-way crossover phase to evaluate safety and efficacy of lisdexamfetamine dimesylate in the adult workplace environment was conducted. Clinical assessments included the ADHD Impact Module for Adults (AIM-A) to assess the effect of lisdexamfetamine dimesylate on perception of quality of life and the Clinical Global Impressions-Severity/Improvement to assess symptom severity at baseline and improvement over time. Safety assessments included physical examination, treatment-emergent adverse events, vital signs, and electrocardiogram measurements. RESULTS: Questions 1 and 4 of the AIM-A suggest improvement from baseline in overall quality of life at week 4 with lisdexamfetamine dimesylate treatment. Post-hoc analysis revealed no significant differences attributable to either age or sex. Overall responses to questions 2 and 3, which related to overall life goals, did not change in a majority of participants during the 4-week open-label phase of this study. For all lisdexamfetamine dimesylate doses combined, treatment-emergent adverse events occurring in ≥ 5% of participants during the dose-optimization phase were decreased appetite (36.6%), dry mouth (30.3%), headache (19.7%), insomnia (18.3%), upper respiratory tract infection (9.9%), irritability (8.5%), nausea (7.7%), anxiety (5.6%), and feeling jittery (5.6%). CONCLUSIONS: At the end of the dose-optimization phase, lisdexamfetamine dimesylate treatment suggested quality of life improvements in adults with ADHD, with a safety profile consistent with long-acting stimulant use.

Effect size of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine duration of efficacy of lisdexamfetamine dimesylate (LDX) in adults with attention-deficit/hyperactivity disorder (ADHD) by effect size in performance and symptom improvement in a simulated adult workplace environment (AWE). METHODS: Adults (aged 18-55 years) with ADHD enrolled in the AWE study of LDX with open-label dose-optimization and randomized, placebo-controlled, double-blind, 2-way crossover phases. Efficacy measures included the Permanent Product Measure of Performance (PERMP)-Attempted (-A) and PERMP-Correct (-C) scores assessed throughout the day and the ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts. Model-based least-squares (LS) mean effect size was assessed for PERMP and post-hoc ADHD-RS-IV with adult prompts. Remission was defined as an ADHD-RS-IV total scores ≤ 18. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs. RESULTS: Least-squares mean (standard error [SE]) effect sizes were 0.9 (0.17) for PERMP-A and 0.8 (0.16) for PERMP-C for all postdose sessions. For PERMP-A, postdose LS mean (SE) effect sizes were 0.5 (0.15), 0.8 (0.16), 0.7 (0.16), 0.7 (0.16), 0.7 (0.16), and 0.6 (0.16) at 2, 4, 8, 10, 12, and 14 hours, respectively. Medium-to-large effect sizes (0.5-0.8) were generally maintained from 2 to 14 hours for all PERMP assessments. Overall LS mean (SE) ADHD-RS-IV total and subscale effect sizes were -1.2 (0.19), -1.2 (0.19), and -1.0 (0.17), respectively. Remission was achieved in 67.6% of participants receiving LDX. Treatment-emergent adverse events (≥ 5% with LDX) during the 4-week dose-optimization phase were decreased appetite, dry mouth, headache, insomnia, upper respiratory tract infection, irritability, nausea, anxiety, and feeling jittery. During the crossover week on LDX, there were no TEAEs ≥ 5%. CONCLUSIONS: In adults studied in the AWE, medium-to-large model-based effect sizes were maintained from 2 to 14 hours postdose, on a performance-based measure of productivity, suggesting participants experienced improvement in sustained attention throughout the day and into the evening hours. Lisdexamfetamine dimesylate demonstrated a safety profile consistent with long-acting stimulants.