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Objective: To compare the dose effects of long-acting extended-release dexmethylphenidate (ER d-MPH) and ER mixed amphetamine salts (ER MAS) on attention-deficit/hyperactivity disorder (ADHD) symptom dimensions, global and specific impairments, and common adverse events associated with stimulants. Methods: Fifty-six children and adolescents with ADHD participated in an 8-week, double-blind, crossover study comparing ER d-MPH (10, 20, 25–30 mg) and ER MAS (10, 20, 25–30) with a week of randomized placebo within each drug period. Efficacy was assessed with the ADHD Rating Scale-IV (ADHD-RS-IV), whereas global and specific domains of impairment were assessed with the Clinical Global Impressions Severity and Improvement Scales and the parent-completed Weiss Functional Impairment Scale, respectively. Insomnia and decreased appetite, common stimulant-related adverse events, were measured with the parent-completed Stimulant Side Effects Rating Scale. Results: Both ER d-MPH and ER MAS were associated with significant reductions in ADHD symptoms. Improvement in Total ADHD and Hyperactivity/Impulsivity symptoms were strongly associated with increasing dose, whereas improvements in Inattentive symptoms were only moderately associated with dose. About 80% demonstrated reliable change on ADHD-RS-IV at the highest dose level of ER MAS compared with 79% when receiving ER d-MPH. Decreased appetite and insomnia were more common at higher dose levels for both stimulants. Approximately 43% of the responders were preferential responders to only one of the stimulant formulations. Conclusions: Dose level, rather than stimulant class, was strongly related to medication response.

Musicians spend considerable time practicing to acquire, refine, and maintain performance skills. Because practice is a necessary part of music learning, researchers have investigated practice to determine how musicians’ efforts can be optimized in terms of time and behavior. The energy musicians can expend in any one practice session is finite, limited by both mental and physical fatigue, so rest has always been important as a means of recovering from effortful work. But recent research makes clear that rest benefits human learning in multi-faceted ways that extend beyond recovery, and these ideas are underrepresented in music research.This dissertation examined rest in two ways. First, I explored rest using a motor learning framework common in memory consolidation research. Researchers have examined the performance of nonmusicians learning various motor sequence tasks and documented more performance gain following 10-s intervals of rest than after 10-s intervals of practice, attributing rest gains to memory consolidation mechanisms initiated early in learning. In the first of two studies presented in Chapter 2, I explored previously published data (Simmons et al., 2019) to compare speed gains made during alternating 30-s intervals of practice and rest between musician and non-musician groups as they learned a five-element motor sequence task. Both groups made significant improvements in performance speed, although musicians outperformed nonmusicians consistently. Participants’ overall speed gains were equally attributable to practice and rest intervals, which is inconsistent with the idea that more gains are attributable to early-stage consolidation than to practice in initial skill acquisition.In the second study of Chapter 2, I used the same consolidation protocol to determine whether the duration of practice and rest intervals affected musicians’ speed gains as they acquired a new motor skill. I compared two schedules of alternating practice and rest (10 s or 30 s) and observed similar significant speed gains in the two schedule conditions. I found only one significant difference between gains attributable to practice and rest in the first 30 s of practice; specifically, significantly greater gains were demonstrated by the 30-s group in their first practice interval than in any other interval of practice or rest in both groups. This result further contradicts the idea that early-stage consolidation contributes more to overall performance gain than physical practice.The second approach to examining rest in music learning was to document how rest occurs naturally in the practice of highly skilled collegiate musicians as they maintain and refine previously acquired motor skills. Study 3’s exploratory observational design (see Chapter 3) included an examination of 25 20-min practice videos collected as part of an instrumental pedagogy course for music performance majors. I found that participants spent 31.5% of their total practice time engaging in behaviors other than full-instrument performance. Six of the 25 participants did not rest—even briefly—during their 20-min video, and three more rested once. These results make clear that the music majors within this sample are not consistently including rest as a systematic tool that can facilitate changes in performance. This was the first study to include detailed documentation of practice behaviors other than full instrument performance, and I have defined and described these behaviors so they may be useful for future research.Perhaps the most compelling result of this work is that it provides evidence about the benefits of rest in ways that could encourage musicians to be intentional about including time away from playing in their practice. When rest is employed strategically, it benefits motor learning in music by offering physical relief and creating moments for reflection and goal setting between performance trials; even in the earliest stages of skill acquisition, time away from physical practice allows mechanisms of consolidation to modify memory.

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; β*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; β*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery–Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t32 = 0.11, p = 0.91, 95% CI [−7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.

Biological collections house millions of specimens with digital images increasingly available through open‐access platforms. However, most imaging protocols were developed for human interpretation without considering automated analysis requirements. As computer vision applications revolutionize taxonomic identification and trait extraction, a critical gap exists between current digitization practices and computational analysis needs. This review provides the first comprehensive practical framework for optimizing biological specimen imaging for computer vision applications. Through interdisciplinary collaboration between taxonomists, collection managers, ecologists and computer scientists, we synthesized evidence‐based recommendations addressing fundamental computer vision concepts and practical imaging considerations. We provide immediately actionable implementation guidance while identifying critical areas requiring community standards development. Our framework encompasses 10 interconnected considerations for optimizing image capture for computer vision‐powered taxonomic identification and trait extraction. We translate these into practical implementation checklists, equipment selection guidelines and a roadmap for community standards development, including filename conventions, pixel density requirements and cross‐institutional protocols. By bridging biological and computational disciplines, this approach unlocks automated analysis potential for millions of existing specimens and guides future digitization efforts towards unprecedented analytical capabilities.

RNA editing critically regulates neurodevelopment and normal neuronal function. The global landscape of RNA editing was surveyed across 364 schizophrenia cases and 383 control postmortem brain samples from the CommonMind Consortium, comprising two regions: dorsolateral prefrontal cortex and anterior cingulate cortex. In schizophrenia, RNA editing sites in genes encoding AMPA-type glutamate receptors and postsynaptic density proteins were less edited, whereas those encoding translation initiation machinery were edited more. These sites replicate between brain regions, map to 3′-untranslated regions and intronic regions, share common sequence motifs and overlap with binding sites for RNA-binding proteins crucial for neurodevelopment. These findings cross-validate in hundreds of non-overlapping dorsolateral prefrontal cortex samples. Furthermore, ~30% of RNA editing sites associate with cis-regulatory variants (editing quantitative trait loci or edQTLs). Fine-mapping edQTLs with schizophrenia risk loci revealed co-localization of eleven edQTLs with six loci. The findings demonstrate widespread altered RNA editing in schizophrenia and its genetic regulation, and suggest a causal and mechanistic role of RNA editing in schizophrenia neuropathology.

Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs. Structural variants (SVs) contribute to the genetic architecture of many brain-related disorders. Here, the authors integrate SV calls from genome sequencing (n = 755) with RNA-seq data (n = 629) from post-mortem dorsal lateral prefrontal cortex to annotate the gene regulatory effects of SVs in the human brain and their potential to contribute to disease.

Ethanol is an antagonist of the N -methyl- D -aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.