Task-evoked changes in pupil dilation have long been used as a physiological index of cognitive effort. Unlike this response, that is measured during or after an experimental trial, the baseline ...pupil dilation (BPD) is a measure taken prior to an experimental trial. As such, it is considered to reflect an individual's arousal level in anticipation of an experimental trial. We report data for 68 participants, ages 18 to 89, whose hearing acuity ranged from normal hearing to a moderate hearing loss, tested over a series 160 trials on an auditory sentence comprehension task. Results showed that BPDs progressively declined over the course of the experimental trials, with participants with poorer pure tone detection thresholds showing a steeper rate of decline than those with better thresholds. Data showed this slope difference to be due to participants with poorer hearing having larger BPDs than those with better hearing at the start of the experiment, but with their BPDs approaching that of the better hearing participants by the end of the 160 trials. A finding of increasing response accuracy over trials was seen as inconsistent with a fatigue or reduced task engagement account of the diminishing BPDs. Rather, the present results imply BPD as reflecting a heightened arousal level in poorer-hearing participants in anticipation of a task that demands accurate speech perception, a concern that dissipates over trials with task success. These data taken with others suggest that the baseline pupillary response may not reflect a single construct.
Studies of spoken word recognition have reliably shown that both younger and older adults' recognition of acoustically degraded words is facilitated by the presence of a linguistic context. Against ...this benefit, older adults' word recognition can be differentially hampered by interference from other words that could also fit the context. These prior studies have primarily used off-line response measures such as the signal-to-noise ratio needed for a target word to be correctly identified. Less clear is the locus of these effects; whether facilitation and interference have their influence primarily during response selection, or whether their effects begin to operate even before a sentence-final target word has been uttered. This question was addressed by tracking 20 younger and 20 older adults' eye fixations on a visually presented target word that corresponded to the final word of a contextually constraining or neutral sentence, accompanied by a second word on the computer screen that in some cases could also fit the sentence context. Growth curve analysis of the time-course of eye-gaze on a target word showed facilitation and inhibition effects begin to appear even as a spoken sentence is unfolding in time. Consistent with an age-related inhibition deficit, older adults' word recognition was slowed by the presence of a semantic competitor to a degree not observed for younger adults, with this effect operating early in the recognition process.
There is considerable evidence that listeners' understanding of a spoken sentence need not always follow from a full analysis of the words and syntax of the utterance. Rather, listeners may instead ...conduct a superficial analysis, sampling some words and using presumed plausibility to arrive at an understanding of the sentence meaning. Because this latter strategy occurs more often for sentences with complex syntax that place a heavier processing burden on the listener than sentences with simpler syntax, shallow processing may represent a resource conserving strategy reflected in reduced processing effort. This factor may be even more important for older adults who as a group are known to have more limited working memory resources. In the present experiment, 40 older adults (
= 75.5 years) and 20 younger adults (
= 20.7) were tested for comprehension of plausible and implausible sentences with a simpler subject-relative embedded clause structure or a more complex object-relative embedded clause structure. Dilation of the pupil of the eye was recorded as an index of processing effort. Results confirmed greater comprehension accuracy for plausible than implausible sentences, and for sentences with simpler than more complex syntax, with both effects amplified for the older adults. Analysis of peak pupil dilations for implausible sentences revealed a complex three-way interaction between age, syntactic complexity, and plausibility. Results are discussed in terms of models of sentence comprehension, and pupillometry as an index of intentional task engagement.
Background
Individuals using onabotulinumtoxinA as a preventive migraine treatment often use acute treatments for breakthrough attacks. Data on real-world effectiveness of the small-molecule ...calcitonin gene–related peptide (CGRP) receptor antagonist ubrogepant in combination with onabotulinumtoxinA are limited.
Methods
COURAGE, a prospective, multiple attack, observational study, evaluated the real-world effectiveness of ubrogepant (50 or 100 mg) for acute treatment of migraine in people receiving onabotulinumtoxinA, an anti-CGRP monoclonal antibody (mAb), or both. This analysis focused only on onabotulinumtoxinA users. The Migraine Buddy app was used to identify eligible participants and track response to treated attacks. For each ubrogepant-treated attack, meaningful pain relief (MPR) and return to normal function (RNF) at 2 and 4 h post-dose over 30 days was assessed. MPR was defined as a level of relief that is meaningful to the participant, usually occurring before the pain is all gone. After 30 days, satisfaction was reported on a 7-point scale and overall acute treatment optimization was evaluated using the migraine Treatment Optimization Questionnaire-4 (mTOQ-4).
Results
This analysis included 122 participants who received ubrogepant and onabotulinumtoxinA and reported on 599 ubrogepant-treated attacks. Following the first ubrogepant-treated attack, MPR was achieved in 53.3% of participants 2 h post-dose and in 76.2% of participants 4 h post-dose. RNF was achieved in 25.4% of participants 2 h post-dose and in 45.9% of participants 4 h post-dose. MPR and RNF results were similar across up to 10 ubrogepant-treated attacks. After 30 days, satisfaction with ubrogepant in combination with onabotulinumtoxinA was reported by 69.8% of participants and acute treatment optimization (defined as mTOQ-4 score ≥ 4) was achieved in 77.6%.
Conclusions
In this prospective real-world effectiveness study, ubrogepant treatment in onabotulinumtoxinA users with self-identified migraine was associated with high rates of MPR and RNF at 2 and 4 h as well as satisfaction and acute treatment optimization. Although the lack of a contemporaneous control group limits causal inference, these findings demonstrate the feasibility of using a novel, app-based design to evaluate the real-world effectiveness and satisfaction of treatments.
Graphical Abstract
A theoretical endpoint staging framework was previously developed and published, aligning outcomes (i.e., memory) to the stage of Alzheimer's disease (AD) in which a given outcome is most relevant ...(i.e., has the greatest risk of degradation). The framework guides the selection of endpoints measuring outcomes relevant within a target AD population. Here, a proof of concept is presented via post-hoc analyses of the Alzheimer Management by Albumin Replacement (AMBAR) Phase 2b clinical trial in patients with AD (NCT01561053, 2012).
To evaluate whether aligning endpoints measuring cognition, function, and quality of life to hypothesized 'target' stages of AD yields magnitudes of treatment efficacy greater than those reported in the AMBAR full analysis set (FAS).
Three endpoints were tested: ADAS-Cog 12, ADCS-ADL, and QoL-AD. The magnitude of treatment efficacy was hypothesized to be maximized in the target stages of mild, mild-to-moderate, and very mild AD, respectively, compared to the full analysis set (FAS) and non-target stages.
For ADAS-Cog 12, the magnitude of treatment efficacy was largest in the non-target stage (-4.0, p = 0.0760) compared to target stage and FAS. For ADCS-ADL and QoL-AD, the magnitude of treatment efficacy was largest in the target stage (14.2, p = 0.0003; 2.4, p < 0.0001, respectively) compared to non-target stage and FAS.
Findings indicated that evaluating endpoints in the most relevant AD stage can increase the magnitude of the observed treatment efficacy. Evidence provides preliminary proof of concept for the endpoint staging framework.
Introduction
Although acute and preventive treatments for migraine are commonly given in combination, data on the real-world effectiveness of ubrogepant as an acute treatment when used with an ...anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (with or without onabotulinumtoxinA) are limited. This analysis sought to evaluate the real-world effectiveness, treatment satisfaction, and optimization of ubrogepant for the acute treatment of migraine when used in combination with an anti-CGRP monoclonal antibody, with or without concomitant onabotulinumtoxinA.
Methods
This prospective, multiple-attack, open-label, observational study (COURAGE) assessed meaningful pain relief (MPR), return to normal function (RNF), treatment satisfaction, and acute treatment optimization of ubrogepant (50 or 100 mg) when combined with an anti-CGRP monoclonal antibody, onabotulinumtoxinA, or both in adult users of Migraine Buddy, a migraine tracking application.
Results
In the ubrogepant and anti-CGRP monoclonal antibody arm (
n
= 245), following the first ubrogepant-treated attack, 61.6% (151/245) and 80.4% (197/245) of ubrogepant-treated participants achieved MPR at 2 and 4 h post-dose, respectively, and 34.7% (85/245) and 55.5% (136/245) achieved RNF at 2 and 4 h post-dose, respectively. Across up to 10 ubrogepant-treated attacks (
N
= 1153), MPR was achieved in 51.3% (592/1153) and 73.5% (847/1153) at 2 and 4 h post-dose, respectively. RNF was achieved by 32.2% (371/1153) and 53.2% (613/1153) at 2 and 4 h post-dose. After 30 days, 72.7% (168/231) of participants reported satisfaction (using a 7-point scale) with ubrogepant when used in combination with an anti-CGRP monoclonal antibody, and 79.7% (184/231) of participants achieved acute treatment optimization (defined as moderate-maximum treatment efficacy using the Migraine Treatment Optimization Questionnaire-4).
Conclusion
Real-world ubrogepant use with an anti-CGRP monoclonal antibody was associated with MPR, RNF, satisfaction, and acute treatment optimization.
The aging process includes a number of cognitive changes (e.g. reduced working memory capacity, reduced effectiveness of inhibitory control abilities, slowed processing) that can affect older adults’ ...ability to comprehend speech. At the sensory level, adult aging is also often accompanied by reduced hearing acuity. Speech processing occurs on multiple levels, each accompanied by a unique set of difficulties for the older listener, from sensory to cognitive. As a consequence, even when speech recognition is successful, this success may come at the cost of cognitive resources that might otherwise be available for higher-level comprehension of sentences and discourse, especially when the meaning is expressed with complex syntax. Thus, age-related effects are seen primarily when speech comprehension is made more difficult and the processing demands are increased by, for example, degraded acoustic features, increased syntactic complexity, or decreased context. A major limitation in the field is the common use of off-line measurements such as button-press reaction times or verbal responses. Given that with aging comes motor slowing and changes in decision-making, these measures may not be accurate representations of true age-related changes in speech comprehension. This dissertation reports a series of 6 experiments that address three specific aims. (1) To isolate the effects of cognitive aging on on-line speech comprehension, in contrast with off-line measures. The visual world paradigm (VWP) was used to contrast the timing of eye fixations with latencies to overt responses, finding differential effects of aging on overt response latencies compared to eye gaze. The VWP was also used to examine the conditions under which older adults show differential slowing in their comprehension as measured by eye gaze. (2) To investigate how effort allocation algorithms underlying speech comprehension performance vary even when performance does not. Sentences were used that vary in complexity, and the task-evoked pupil response (TEPR) was measured to study how performance on measures of comprehension accuracy compares to expended effort. A divergence between performance and expended effort was found, as well as a tipping point at which older adults in particular are either unable or unwilling to continue to increase their expended effort. (3) To describe the effects of increased perceptual effort, as caused by variations in hearing acuity, on speech comprehension performance and effort allocation, and to determine the extent to which these effects are unique to age-related hearing loss. Over a series of three experiments, the effects of hearing acuity, controlling for age, were examined on the accuracy of speech comprehension and the effort required for it (as measured by pupillometry). Poorer hearing often predicted generally higher effort, and differential effects on accuracy when sentences were more complex. Finally, a larger group of normal-hearing younger adults was examined, and similar differential effects of elevated hearing thresholds on sentences with more complex syntax were found. This finding was surprising but demonstrated that the effects of perceptual effort observed in older adults with poor hearing is not unique to the aging population or to those with clinically significant hearing loss.
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