Greater adolescent tiredness is related to more emotional arousal during a hyperventilation task: An area under the curve approach.

INTRODUCTION: Approximately 36% of adolescents report sleep problems (Crowley et al., 2018). Understanding the relation between sleep and emotional experience is crucial in understanding the high incidence of mental health concerns during adolescence. The current study sought to expand understanding in the area by testing the hypothesis that baseline tiredness ratings would predict greater emotional arousal and negative valence across the course of emotional response elicited by a voluntary hyperventilation procedure. METHODS: A community sample of 110 youth (10-18 years; 47.8% girls) provided baseline tiredness ratings and ratings of emotional valence and arousal, 2 min before, immediately after, and 3 min after a hyperventilation task. The area under the curve (AUC) was calculated using the repeated measures of valence and arousal, and correlations between the response curves and baseline tiredness were examined. RESULTS AND CONCLUSIONS: Findings indicated baseline tiredness was positively associated with AUC arousal (r = 0.23), but not valence. This suggests daytime tiredness is associated with the degree of emotional arousal elicited by a psychobiological stressor. By extension, adolescents may experience more arousing emotional reactions when tired, and thus the common sleep deprivation observed during this developmental period may increase risk for mental health problems associated with elevated emotional reactivity.

A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study).

OBJECTIVE: The objective of this study was to evaluate differences in the pharmacodynamic (PD) profile of 2 second-generation extended-release (ER) formulations of methylphenidate (MPH): Metadate CD (MCD; methylphenidate HCl, US Pharmacopeia) extended-release capsules, CII, and Concerta (CON; methylphenidate HCl) extended-release tablets, CII. Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior. Previous studies have shown that the near-equal doses of MCD and CON provide equivalent, total exposure to MPH as measured by area under the plasma concentration time curve, yet their pharmacokinetic (PK) plasma concentration versus time profiles are different. We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes: 1) an initial bolus dose of immediate-release (IR) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing, which for the MCD capsule is delivered by 30% of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22% of the total daily dose; and 2) an extended, controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus, which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system. According to this PK/PD model, clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration. METHODS: This was a multisite, double-blind, double-dummy, 3-way crossover study of 2 active treatments (MCD and CON) and placebo (PLA). Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low (20 mg of MCD and 18 mg of CON), medium (40 mg of MCD and 36 mg of CON), or high (60 mg of MCD and 54 mg of CON), and in a randomized order each of the study treatments was administered once daily in the morning for 1 week. On the seventh day of each treatment week, children attended a laboratory school, where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals. Safety was assessed by patient reports of adverse events, parent ratings on a stimulant side-effects scale, and measurement of vital signs. RESULTS: The analyses of variance revealed large, statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures (deportment, attention, and permanent product). The interactions of treatment x session were also highly significant for all 3 outcome measures. Inspection of the PD profiles for the treatment x session interactions suggested 4 patterns of efficacy across the day: 1) PLA > MCD approximately CON (PLA superiority) immediately after dosing; 2) MCD > CON > PLA during the morning (MCD superiority); 3) MCD approximately CON > PLA during the afternoon (PD equivalence of MCD and CON); and 4) CON > MCD approximately PLA in the early evening (CON superiority). The effect of site was significant, because some study centers had low and some high scores for behavior in the lab classroom, but both the low- and high-scoring sites showed similar PD patterns across the day. The interaction of dose x treatment was not significant, indicating that the pattern of treatment effects was consistent across each dose level. There were no statistically significant overall differences among the 3 treatments for the frequency of treatment-emergent adverse events, ratings of side effects, or vital signs. Two additional PK/PD questions were addressed: 1. The a priori hypothesis called for a comparison of the average of sessions (removing session as a factor) during a time period that corresponds to the length of a typical school day (from 1.5 through 7.5 hours after dosing). For the planned contrast of the 2 treatment conditions (MCD versus CON), the difference was significant, confirming the a priori hypothesis of superiority of near-equal daily doses of MCD over CON for this predefined postdosing period. 2. In the design of the study, the dose factor represented the total daily dose, consisting of 2 components: the initial bolus doses of IR MPH, which differ for the near-equal total daily doses of MCD and CON, and the reservoir doses of ER MPH, which were the same for the 2 formulations. To evaluate the moderating effects of the bolus component of dose on outcome, average effect size (ES) was calculated for the efficacy outcomes at the time of expected peak PK concentration times of the initial bolus component for each formulation at the 3 dose levels. The correlation (r) of ES with IR MPH bolus dose was significant for each of the 3 outcome measures (r approximately .9), indicating that the magnitude of effects in the early morning may be attributed to the dose administered by the IR MPH bolus of each formulation. For the 2 dose conditions with equal 12-mg IR MPH boluses (MCD 40 and CON 54), the ESs were large and indistinguishable (eg, deportment ES approximately 0.75 for both). CONCLUSIONS: Once-daily doses of MCD and CON produced statistically significantly different PD effects on surrogate measures of behavior and performance among children with attention-deficit/hyperactivity disorder in the laboratory school setting. As predicted by the PK/PD model, superiority at any point in time was achieved by the formulation with the highest expected plasma MPH concentration.

Visual identification and spatial location in Alzheimer's disease.

Twelve patients with Alzheimer's disease (AD) and 15 healthy elderly control subjects were shown sets of luminance-defined letters, texture-defined letters, luminance-defined squares, and texture-defined squares. They were asked to name the letters or point to the target square on each page. The stimuli were graded into four levels of difficulty based on the amount of contrast between the figure and the background. Performance was measured in terms of the maximum level of difficulty at which the participant correctly identified or located the three figures. Contrary to expectations, no significant difference was found between the performance of AD patients and control subjects on texture discrimination tasks vs. luminance discrimination tasks. However, results indicate that AD patients are impaired in performing a task requiring them to locate a texture-defined target of known shape in a noisy background field. By contrast, AD patients show no significant deficit in a task requiring them to locate a texture-defined shape in a known location. This argues that the observed deficit in the location task is not due to a failure in the system that discriminates target texture from background texture (since both location and identification tasks require the same textural discriminations), but rather to an impairment of the system responsible for "finding things" (i.e., locating known targets at unknown locations). This observation suggests that AD patients may suffer selective damage to the dorsal "Where" pathway, which is responsible for localizing objects in space.