An n-of-1 trial service in clinical practice: Testing the effectiveness of stimulants for attention-deficit/hyperactivity disorder

OBJECTIVE. We sought to describe the clinical use of n-of-1 trials for attention-deficit/hyperactivity disorder in publicly and privately funded family and specialized pediatric practice in Australia. METHODS. We used a within-patient randomized, double-blind, crossover comparison of stimulant (dexamphetamine or methylphenidate) versus placebo or alternative stimulant using 3 pairs of treatment periods. Trials were conducted from a central location using mail and telephone communication, with local supervision by the patients' clinicians. PATIENTS. Our study population included children with clinically diagnosed attention-deficit/ hyperactivity disorder who were aged 5 to 16 years and previously stabilized on an optimal dose of stimulant. They were selected because treatment effectiveness was uncertain. MAIN OUTCOME MEASURES. Our measures included number of patients recruited, number of doctors who used the service, geographic spread, completion rates, response rate, and post-n-of-1 trial decisions. RESULTS. Forty-five doctors across Australia requested 108 n-of-1 trials, of which 86 were completed. In 69 drug-versus-placebo comparisons, 29 children responded better to stimulant than placebo. Immediately posttrial, 19 of 25 drug-versus-placebo responders stayed on the same stimulant, and 13 of 24 nonresponders ceased or switched stimulants. In 40 of 63 for which data were available, posttrial management was consistent with the trial results. For all types of n-of-1 trials, management changed for 28 of 64 children for whom information was available. DISCUSSION. Attention-deficit/hyperactivity disorder n-of-1 trials can be implemented successfully by mail and telephone communication. This type of trial can be valuable in clarifying treatment effect when it is uncertain, and in this series, they had a noticeable impact on short-term management.

A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis

Objectives: The antiinflammatory effect of macrolide antibiotics has been well-established, as has their role in the treatment of certain disorders of chronic airway inflammation. Several studies have suggested that long-term, low-dose macrolides may be efficacious in the treatment of chronic rhinosinusitis; however, these studies have lacked a control group. To date, this effect has not been tested in a randomized, placebo-controlled study. Method: The authors conducted a double-blind, randomized, placebo-controlled clinical trial on 64 patients with chronic rhinosinusitis. Subjects received either 150 mg roxithromycin daily for 3 months or placebo. Outcome measures included the Sinonasal Outcome Test-20 (SNOT-20), measurements of peak nasal inspiratory flow, saccharine transit time, olfactory function, nasal endoscopic scoring, and nasal lavage assays for interleukin-8, fucose, and a2-macroglobulin. Results. There were statistically significant improvements in SNOT-20 score, nasal endoscopy, saccharine transit time, and IL-8 levels in lavage fluid (P < .05) in the macrolide group. A correlation was noted between improved outcome measures and low IgE levels. No significant improvements were noted for olfactory function, peak nasal inspiratory flow, or lavage levels for fucose and a2-macroglobulin. No improvement in any outcome was noted in the placebo-treated patients. Conclusion: These findings suggest that macrolides may have a beneficial role in the treatment of chronic rhinosinusitis, particularly in patients with low levels of IgE, and supports the in vitro evidence of their antiinflammatory activity. Additional studies are required to assess their place in clinical practice.

Associative knowledge controls deployment of visual selective attention

According to some models of visual selective attention, objects in a scene activate corresponding neural representations, which compete for perceptual awareness and motor behavior. During a visual search for a target object, top-down control exerted by working memory representations of the target's defining properties resolves competition in favor of the target. These models, however, ignore the existence of associative links among object representations. Here we show that such associations can strongly influence deployment of attention in humans. In the context of visual search, objects associated with the target were both recalled more often and recognized more accurately than unrelated distractors. Notably, both target and associated objects competitively weakened recognition of unrelated distractors and slowed responses to a luminance probe. Moreover, in a speeded search protocol, associated objects rendered search both slower and less accurate. Finally, the first saccades after onset of the stimulus array were more often directed toward associated than control items.

Attention deficits in dyslexia:Evidence for an automatisation deficit?

Both attentional difficulties and rapid processing deficits have recently been linked with dyslexia. We report two studies comparing the performance of dyslexic and control teenagers on attentional tasks. The two studies were based on two different conceptions of attention. Study 1 employed a design that allowed three key components of attention - focusing, switching, and sustaining - to be investigated separately. One hypothesis under investigation was that rapid processing problems - in particular impaired ability to switch attention rapidly - might be associated with dyslexia. However, although dyslexic participants were significantly less accurate than their controls in a condition where they had to switch attention between two target types, the nature of the deficit suggested that the problem was not in switching attention per se. Thus, in Study 2, we explored an alternative interpretation of the Study 1 results in terms of the classic capacity-limited models of "central" attention. We contrasted two hypotheses: (1) that dyslexic teenagers have reduced cognitive resources versus (2) that they suffer from a general impairment in the ability to automatise basic skills. To investigate the automaticity of the shape recognition component of the task a similar attention paradigm to that used in Study 1 was employed, but using degraded, as well as intact, stimuli. It was found that stimulus degradation led to relatively less impairment for dyslexic than for matched control groups. The results support the hypothesis that dyslexic people suffer from a general impairment in the ability to automatise skills - in this case the skill of automatic shape recognition.

The role of prior exposure on the capture of attention by items in working memory

The Biased Competition Model (BCM) suggests both top-down and bottom-up biases operate on selective attention (e.g., Desimone & Duncan, 1995). It has been suggested that top-down control signals may arise from working memory. In support, Downing (2000) found faster responses to probes presented in the location of stimuli held vs. not held in working memory. Soto, Heinke, Humphreys, and Blanco (2005) showed the involuntary nature of this effect and that shared features between stimuli were sufficient to attract attention. Here we show that stimuli held in working memory had an influence on the deployment of attentional resources even when: (1) It was detrimental to the task, (2) there was equal prior exposure, and (3) there was no bottom-up priming. These results provide further support for involuntary top-down guidance of attention from working memory and the basic tenets of the BCM, but further discredit the notion that bottom-up priming is necessary for the effect to occur.

Laterality differences in memory and attention

A critical review of the auditory selective attention literature is presented, particular reference is made to methodological issues arising from the asymmetrical hemispheric representation of language in the context of the dominant research technique dichotic shadowing. Subsequently the concept of cerebral localization is introduced, and the experimental literature with reference to models of laterality effects in speech and audition discussed. The review indicated the importance of hemispheric asymmetries insofar as they might influence the results of dichotic shadowing tasks. It is suggested that there is a potential overlap between models of selective attention and hemispheric differences. In Experiment I, ~ a key experiment in auditory selective attention is replicated and by exercising control over possible laterality effects some of the conflicting results of earlier studies were reconciled. The three subsequent experiments, II, III and IV, are concerned with the recall of verbally shadowed inputs. A highly significant and consistent effect of ear of arrival upon the serial position of items recalled is reported. Experiment V is directed towards an analysis of the effect that the processing of unattended inputs has upon the serial position of attended items that are recalled. A significant effect of the type of unattended material upon the recall of attended items was found to be influenced by the ear of arrival of inputs. In Experiment VI, differences between the two ears as attended and unattended input channels were clarified. Two main conclusions were drawn from this work. First, that the dichotic shadowing technique cannot control attention. Instead the task aprocessing both channels of dichotic inputs is unevenly shared bet\'reen the hemispheres as a function of the ear shadowed. Consequently, evidence for the processing of unattended information is considered in terms of constraints imposed by asymmetries in the functional organization of language, not in terms of a limited processing capacity model. The second conclusion to be drawn is that laterality differences can be effectively examined using the dichotic shadowing technique, a new model of laterality differences is proposed and discussed.

Behavioural and neuroimaging investigations of the relationship between visual attention, affordance and action

In this thesis the relationship between visual attention, affordance and action was investigated using a combination of neuroimaging and behavioural studies. Neuronal activity and movement construction were assessed when individuals passively viewed or produced action towards stimuli varying in their affordance and/or attentional attributes. The main findings were: (i) the passive perception of both object and abstract visual patterns was associated with decreased alpha and/or beta activity in sensori-motor cortex, occipito-temporal cortex and cerebellum. These are brain regions associated with the planning and production of visually guided action; (ii) for object patterns, decreased alpha and beta activity was also observed in regions of superior parietal and premotor cortex. These regions contain neurons argued to be essential for matching hand kinematics with manipulate objects; and (iii) in both control participants and a deafferented individual, studies of planned and unplanned pointing manoeuvres revealed that the attentional bias of a stimulus was critical for fast, efficient action production whereas the affordance bias was critical in determining end-point accuracy. Taken together, these findings demonstrate that affordance is not a necessary prerequisite for the potential of motor codes. Rather, affordance enables the construction of motor responses that reflect object functionality and/or manipulability. They further demonstrate that visual attention is associated with the potentiation of motor codes. Indeed, directed visual attention would appear critical for speeded responses. These findings provide new insights into the roles of directed visual attention and affordance upon action.

Impaired sustained attention and executive dysfunction:bipolar disorder versus depression-specific markers of affective disorders

Objective - To identify neurocognitive measures that could be used as objective markers of bipolar disorder. Methods - We examined executive function, sustained attention and short-term memory as neurocognitive domains in 18 participants with bipolar disorder in euthymic state (Beuth), 14 in depressed state (Bdep), 20 with unipolar depression (Udep) and 28 healthy control participants (HC). We conducted four-group comparisons followed by relevant post hoc analyses. Results - Udep and Bdep, but not Beuth showed impaired executive function (p = 0.045 and p = 0.046, respectively). Both Bdep and Beuth, but not Udep, showed impaired sustained attention (p = 0.001 and p = 0.045, respectively). The four groups did not differ significantly on short-term memory. Impaired sustained attention and executive dysfunction were not associated with depression severity, duration of illness and age of illness onset. Only a small number of abnormal neurocognitive measures were associated with medication in Bdep and Beuth. Conclusion - Impaired sustained attention appears specific to bipolar disorder and present in both Beuth and Bdep; it may represent an objective marker of bipolar disorder. Executive dysfunction by contrast, appears to be present in Udep and Bdep and likely represents a marker of depression.

Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin:a randomized, double-blind, placebo-controlled 102-week trial

Background: Management of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.Methods: This was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (=1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.Results: A total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P

Deficient inhibition of return in subclinical OCD only when attention is directed to the threatening aspects of a stimulus

Background - Inhibition of return (IOR) is thought to reflect inhibition of previously attended but irrelevant stimuli. Deficient IOR would increase the likelihood of revisiting previously searched locations or objects, thus leading to unproductive perseverations. Method - Therefore, using a novel IOR task, we investigated whether high scoring checkers attentional biases to threat would result in dysfunctional inhibitory functioning compared to low checkers. In two tasks, we compared 53 subclinical high and 49 low checkers regarding IOR effects for stimuli that were concordant with the concerns of high but not of low checkers (electrical kitchen appliances: e.g., toaster, kettle). The difference between the two tasks was the cueing procedure. In one task, an appliance was switched “ON” and “OFF” as an unpredictive cue, drawing attention to the functionality of the stimulus. Results - In this task, IOR was specifically attenuated in high checkers. In the other task, however, the cue was more abstract in form of a yellow outline that appeared around one of two appliances. Although the appliance was either “ON” or “OFF,” this did not seem to matter and high checkers revealed a typical IOR pattern similar to low checkers. Conclusions - We conclude that IOR mechanisms might not be generally deficient in high checkers; rather only when attention is drawn to the threatening aspects of ecologically valid stimuli, then disengagement of attention is deficient in high checkers. We make suggestions on how our task-specific findings may inform cognitive interventions that target attentional control in the treatment of checking/obsessive–compulsive disorder.

What checkers actually check:an eye tracking study of inhibitory control and working memory

Background - Not only is compulsive checking the most common symptom in Obsessive Compulsive Disorder (OCD) with an estimated prevalence of 50–80% in patients, but approximately ~15% of the general population reveal subclinical checking tendencies that impact negatively on their performance in daily activities. Therefore, it is critical to understand how checking affects attention and memory in clinical as well as subclinical checkers. Eye fixations are commonly used as indicators for the distribution of attention but research in OCD has revealed mixed results at best. Methodology/Principal Finding - Here we report atypical eye movement patterns in subclinical checkers during an ecologically valid working memory (WM) manipulation. Our key manipulation was to present an intermediate probe during the delay period of the memory task, explicitly asking for the location of a letter, which, however, had not been part of the encoding set (i.e., misleading participants). Using eye movement measures we now provide evidence that high checkers’ inhibitory impairments for misleading information results in them checking the contents of WM in an atypical manner. Checkers fixate more often and for longer when misleading information is presented than non-checkers. Specifically, checkers spend more time checking stimulus locations as well as locations that had actually been empty during encoding. Conclusions/Significance - We conclude that these atypical eye movement patterns directly reflect internal checking of memory contents and we discuss the implications of our findings for the interpretation of behavioural and neuropsychological data. In addition our results highlight the importance of ecologically valid methodology for revealing the impact of detrimental attention and memory checking on eye movement patterns.

Modulation of long-range neural synchrony reflects temporal limitations of visual attention in humans

Because of attentional limitations, the human visual system can process for awareness and response only a fraction of the input received. Lesion and functional imaging studies have identified frontal, temporal, and parietal areas as playing a major role in the attentional control of visual processing, but very little is known about how these areas interact to form a dynamic attentional network. We hypothesized that the network communicates by means of neural phase synchronization, and we used magnetoencephalography to study transient long-range interarea phase coupling in a well studied attentionally taxing dual-target task (attentional blink). Our results reveal that communication within the fronto-parieto-temporal attentional network proceeds via transient long-range phase synchronization in the beta band. Changes in synchronization reflect changes in the attentional demands of the task and are directly related to behavioral performance. Thus, we show how attentional limitations arise from the way in which the subsystems of the attentional network interact. The human brain faces an inestimable task of reducing a potentially overloading amount of input into a manageable flow of information that reflects both the current needs of the organism and the external demands placed on it. This task is accomplished via a ubiquitous construct known as “attention,” whose mechanism, although well characterized behaviorally, is far from understood at the neurophysiological level. Whereas attempts to identify particular neural structures involved in the operation of attention have met with considerable success (1-5) and have resulted in the identification of frontal, parietal, and temporal regions, far less is known about the interaction among these structures in a way that can account for the task-dependent successes and failures of attention. The goal of the present research was, thus, to unravel the means by which the subsystems making up the human attentional network communicate and to relate the temporal dynamics of their communication to observed attentional limitations in humans. A prime candidate for communication among distributed systems in the human brain is neural synchronization (for review, see ref. 6). Indeed, a number of studies provide converging evidence that long-range interarea communication is related to synchronized oscillatory activity (refs. 7-14; for review, see ref. 15). To determine whether neural synchronization plays a role in attentional control, we placed humans in an attentionally demanding task and used magnetoencephalography (MEG) to track interarea communication by means of neural synchronization. In particular, we presented 10 healthy subjects with two visual target letters embedded in streams of 13 distractor letters, appearing at a rate of seven per second. The targets were separated in time by a single distractor. This condition leads to the “attentional blink” (AB), a well studied dual-task phenomenon showing the reduced ability to report the second of two targets when an interval <500 ms separates them (16-18). Importantly, the AB does not prevent perceptual processing of missed target stimuli but only their conscious report (19), demonstrating the attentional nature of this effect and making it a good candidate for the purpose of our investigation. Although numerous studies have investigated factors, e.g., stimulus and timing parameters, that manipulate the magnitude of a particular AB outcome, few have sought to characterize the neural state under which “standard” AB parameters produce an inability to report the second target on some trials but not others. We hypothesized that the different attentional states leading to different behavioral outcomes (second target reported correctly or not) are characterized by specific patterns of transient long-range synchronization between brain areas involved in target processing. Showing the hypothesized correspondence between states of neural synchronization and human behavior in an attentional task entails two demonstrations. First, it needs to be demonstrated that cortical areas that are suspected to be involved in visual-attention tasks, and the AB in particular, interact by means of neural synchronization. This demonstration is particularly important because previous brain-imaging studies (e.g., ref. 5) only showed that the respective areas are active within a rather large time window in the same task and not that they are concurrently active and actually create an interactive network. Second, it needs to be demonstrated that the pattern of neural synchronization is sensitive to the behavioral outcome; specifically, the ability to correctly identify the second of two rapidly succeeding visual targets

Placebo expectancy effects in the relationship between glucose and cognition

The present study investigated the extent of expectancy in the ability of glucose to affect cognitive performance. Using a within-subjects design, subjects (n 26) completed four experimental sessions (in counterbalanced order and after an initial practice session) during which they were given a 500 ml drink 30 min prior to completing a cognitive assessment battery. In addition, all subjects completed a baseline practice session during which they were given no drink. During two of the sessions, subjects were given a drink containing 50 g glucose and on the other two they were given a drink containing aspartame. A balanced placebo design was used, such that for half the sessions subjects were accurately informed as to the content of the drink (glucose or aspartame), whereas in the other two sessions they were misinformed as to the content of the drink. The task battery comprised a 6 min visual analogue of the Bakan vigilance task, an immediate verbal free-recall task, an immediate verbal recognition memory task and a measure of motor speed (two-finger tapping). Blood glucose and self-reported mood were also recorded at several time points during each session. Glucose administration was found to improve recognition memory times, in direct contrast to previous findings in the literature. Glucose administration also improved performance on the Bakan task (relative to the control drink), but only in sessions where subjects were informed that they would receive glucose and not when they were told that they would receive aspartame. There were no effects either of the nature of the drink or expectancy on the other measures. These results are interpreted in terms of there being some contribution of expectancy concerning the positive effects of glucose on cognition in studies which have not used an equi-sweet dose of aspartame as a control drink.

The Automation of Adaptive Processes in the System of Distance Education and Knowledge Control

The article reveals a new technological approach to the creation of adaptive systems of distance learning and knowledge control. The use of the given technology helps to automate the learning process with the help of adaptive system. Developed with the help of the quantum approach of knowledge setting, a programming module-controller guarantees the support of students’ attention and the adaptation of the object language, and this helps to provide the effective interaction between learners and the learning system and to reach good results in the intensification of learning process.

Postural control is not systematically related to reading skills:implications for the assessment of balance as a risk factor for developmental dyslexia

Impaired postural control has been associated with poor reading skills, as well as with lower performance on measures of attention and motor control variables that frequently co-occur with reading difficulties. Measures of balance and motor control have been incorporated into several screening batteries for developmental dyslexia, but it is unclear whether the relationship between such skills and reading manifests as a behavioural continuum across the range of abilities or is restricted to groups of individuals with specific disorder phenotypes. Here were obtained measures of postural control alongside measures of reading, attention and general cognitive skills in a large sample of young adults (n = 100). Postural control was assessed using centre of pressure (CoP) measurements, obtained over 5 different task conditions. Our results indicate an absence of strong statistical relationships between balance measures with either reading, cognitive or attention measures across the sample as a whole. © 2014 Loras et al.