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Background Response inhibition, working memory, and response variability are possible endophenotypes of ADHD based on their association with the disorder and evidence of heritability. One of the critical although rarely studied criteria for a valid endophenotype is that it persists despite waxing and waning of the overt manifestations of the disorder, a criterion known as state-independence. This study examined whether these aspects of cognition exhibit state-independence in ADHD. Methods One hundred and seventy-nine children diagnosed with ADHD in a rigorous baseline assessment were contacted for follow-up assessment in adolescence. Of this sample, 130 (73%) were reascertained. At follow-up, children previously diagnosed with ADHD were identified as remittent (n = 24), persistent (n = 64), or in partial remission (n = 42) based on symptoms and impairment of the disorder. Response inhibition, working memory, and response variability were assessed both in childhood (baseline) and adolescence (follow-up) and were compared with age-matched controls (40 children and 28 adolescents) seen at either time point. Results Relative to controls, ADHD children showed baseline deficits in response inhibition, working memory, and response variability. Only the group difference in response inhibition remained significant in adolescence. In general, cognitive performance among ADHD participants improved with age and did so regardless of changes in ADHD symptoms and impairment. Within the ADHD group, however, cognitive performance in childhood and in adolescence did not differ amongst those with persistent, remittent, and partially remittent forms of the disorder. Conclusions Results demonstrate that response inhibition not only distinguishes ADHD children from their unaffected peers but is also state-independent, such that deficits remain present irrespective of changes in the disease phenotype. In other words, inhibitory deficits measured in childhood persist into adolescence even when the ADHD phenotype remits. These findings provide further evidence that the ability to stop prepotent actions is an endophenotype of ADHD.

Individuals with autism spectrum disorder (ASD) often present with deficits in variability in responding across multiple repertoires. However, research to date has resulted in little empirical evaluation of remediation strategies for such deficits. We investigated the effects of lag schedules of reinforcement on response variability using a computer-based task designed for the purpose of the study. The U-value statistic was used as a measure of variability in responding to determine if increasing the lag criterion would correspondingly increase levels of variability. Participants included children with ASD (Group 1) and neurotypical children (Group 2). Results showed that U-values were higher when reinforcement was contingent on increased variability, indicating the effectiveness of higher lag values on response variability. A significant difference in response variability between groups provided evidence for the disparity in such responding in children with ASD compared to their neurotypical peers. Group 1 showed consistently lower U-values than Group 2 indicating lower response variability. However, data from this study clearly show that lag schedules of reinforcement may be employed to increase response variability in ASD.

Human breath can be a complex mixture of trace gases in humid air, with the addition of various anesthetizing agents it becomes even more complex and can present a challenge for the accurate quantification of components. The purpose of this paper was to investigate the quantification of H2S as a function of several potential matrix/interference compounds using negative-ion atmospheric pressure chemical ionization with mass spectrometric detection. Analysis was performed by humidifying zero-air and adding various compounds that would be encountered in a perioperative situation. Nitrous oxide, carbon dioxide and to a lesser extent humidity have significant effects on the instrument response to hydrogen sulfide concentration, while halogenated species were found to have little if any complicating effect. It was found that H2S can be accurately quantified by using either [SO3]− or [SO2]−/[SO3]−, both of which eliminate the response variability due to interferences.

Purpose To evaluate objectively changes in vergence dynamics following intentional visual fatiguing tasks using congruent (C) and non-congruent (NC) vergence stimulus demands. Methods Pre- and post-task vergence dynamics to a 10.3° disparity stimulus were recorded objectively in 12 adult, asymptomatic individuals for both convergence and divergence. There were two fatigue-inducing tasks: Congruent or C-task: Subjects altered bifixation (50 cycles) between reduced Snellen charts at 2 m and at 20 cm every 3 s. Non-congruent or NC task: Subjects performed 50 cycles of vergence flipper (7Δ BO/BI), while bifixating a reduced Snellen chart at 40 cm. Pre- and post-task mean amplitude, time constant, peak velocity, and steady-state response variability were compared. Results There was a significant increase in mean post-task, steady-state response variability for both the C and NC tasks. However, there were no significant group differences for either convergence or divergence between the pre- and post-mean amplitude, time constant, and peak velocity parameters for both the C and NC tasks, although post-task peak velocity was consistently reduced. Conclusions Steady-state vergence response variability was found to be the critical objective parameter to demonstrate significant fatigue effects in the group. Peak velocity was also consistently reduced to a small extent in the NC task. We speculate that these fatigue effects are of a central, and not of peripheral, origin.

Operant response classes are customarily defined in terms of the function of the responses. The function is the effect on the environment which constitutes the contingencies of reinforcement that i...

Lithium is considered to be the prototypical mood stabilizer. Naturalistic studies indicate that about one third of bipolar patients show a good or very good clinical response to lithium therapy. However, based on clinical evaluation, it remains difficult to reliably predict which patients are more likely to benefit from lithium therapy. In the era of personalized medicine, pharmacogenetics offers the hope that genetic markers could provide reliable predictors of individual responses to lithium therapy. As reviewed in this chapter, pharmacogenetic studies performed over the past two decades have unfortunately failed to produce predictive markers for lithium response that are meaningful for clinical practice. Lack of progress may be due to a variety of factors, including small sample sizes, clinical heterogeneity and variable definitions of lithium response versus non-response phenotypes. To circumvent these difficulties, large-scale international collaborative consortia are emerging, thus opening the possibility of performing genome-wide association studies on well-defined lithium-response phenotypes.

Lithium is the leading treatment for relapse prevention in bipolar disorders, but response prediction remains an important challenge for clinicians. Clinical predictors have poor sensitivity and specificity, and biomarkers predicting lithium response are lacking. This chapter reviews future research directions that may improve the prediction of lithium response. One important area for research is investigation of the blood and brain pharmacokinetics of lithium in humans, in particular the identification of the brain regions where lithium exerts its therapeutic action. Consistent data suggest the existence of variations in the lithium concentration between brain regions, but the association between brain lithium distribution and therapeutic response remains to be studied. It is also reasonable to think that active mechanisms at brain barriers underlie the brain distribution of lithium. Finally, a growing body of scientific data is available on the molecular signature of the lithium response, as well as lithium-targeted signalling pathways. All these areas of research are likely to open new avenues for identifying predictive biomarkers of the prophylactic response of lithium, thus facilitating the development of personalized therapeutic strategies.

Consistent performance of anti-drug antibody (ADA) assays through all stages of clinical development is critical for the assessment of immunogenicity and interpretation of PK, PD, safety, and efficacy. The electrochemiluminescent assays commonly employed for ADA measurement use drug conjugated with ruthenium and biotin to bind ADA in samples. Here we report an association between high nonspecific ADA responses in certain drug-naïve individuals and the storage buffer of the conjugated reagents used in a monoclonal antibody ADA assay. Ruthenylated reagents stored in phosphate-buffered saline (PBS) buffer had increased levels of aggregate and produced variable and high baseline responses in some subjects. Reagents stored in a histidine-sucrose buffer (HSB) had lower aggregate levels and produced low sample responses. In contrast to PBS, conjugated reagents formulated in HSB remained low in aggregate content and in sample response variability after 5 freeze/thaw cycles. A reagent monitoring control (RMC) serum was prepared for the real-time evaluation of conjugated reagent quality. Using appropriate buffers for storage of conjugated reagents together with RMCs capable of monitoring of reagent aggregation status can help ensure consistent, long-term performance of ADA methods.

Great response variability caused by genetic and/or environmental factors has been observed among organisms exposed to hazardous chemicals. This subject has been a topic of intense discussion in the USA since President Obama announced support for an “era of precision medicine”, which consists in the inclusion of genetic data of patients in the treatment design, imposing a new approach to risk assessment. Personalized evaluation must consider the phenotypic factors of an individual. Among the markers that have been developed to evaluate any alteration in the structure or function of organisms, biomarkers of susceptibility are of great importance because they indicate the natural characteristics of a given organism which make it more sensitive to a specific adverse effect or disease, or more responsive to exposure to a specific chemical/drug. The ‘-omics’ technologies provide an insight into the relationship between chemical effects and molecular mechanisms of action. These technologies are the pillars for a personalized toxicology and precision medicine. Predictive toxicology requires a more comprehensive knowledge on specific individual factors or susceptibilities predisposing to diseases, enabling personalized risk assessment and adequate medical treatment. Resumo Há uma grande variabilidade nas respostas observadas entre os organismos expostos a uma substância química perigosa. Essa variabilidade é causada por causas genéticas e / ou ambientais. Esse assunto tem sido intensamente discutido, mesmo nos Estados Unidos, desde que o presidente Obama anunciou o apoio a uma “era da medicina de precisão”, a qual consiste na inclusão de dados genéticos do paciente no projeto do tratamento, impondo uma nova abordagem para avaliação de risco. A avaliação personalizada deve considerar fatores fenotípicos de um indivíduo. Entre os biomarcadores que foram desenvolvidos para avaliar qualquer alteração da estrutura ou função do organismo, os biomarcadores de susceptibilidade têm uma grande importância, uma vez que indicam as características naturais de um dado organismo, que o tornam mais sensíveis a um efeito ou doença adversa específica ou em resposta a uma determinada exposição. As tecnologias “ômicas” permitem a compreensão da relação entre os efeitos químicos e dos mecanismos moleculares de ação. Essas tecnologias “ômicas” são os pilares para a toxicologia personalizada e para a medicina de precisão. Toxicologia preditiva exige uma melhor compreensão dos fatores ou susceptibilidades individuais específicas predisponentes a doenças, permitindo uma avaliação de riscos personalizada e um tratamento médico adequado.

In healthy rats, the physiological variation of baseline endothelial function of intrarenal arteries correlates with the severity of renal damage in response to a subsequent specific renal injury. However, whether such a variation in endothelial function may also condition or predict the variable response to angiotensin-converting enzyme-inhibiting treatment in these individuals has not been addressed before. To study this, 5/6 nephrectomy was performed to induce renal injury and chronic kidney disease in a group of healthy Wistar rats. At the time of nephrectomy, interlobar arteries were obtained from the extirpated right kidney and studied in vitro for endothelium-dependent relaxation to acetylcholine. Six weeks thereafter, treatment with lisinopril was started ( n = 11) and continued for 9 wk. Proteinuria (metabolic cages) and systolic blood pressure (SBP; tail cuff) were evaluated weekly, and these were analyzed in relation to renal endothelial function at baseline. 5/6 Nephrectomy induced an increase in SBP and progressive proteinuria. Treatment with lisinopril reduced SBP and slowed proteinuria, albeit to a variable degree among individuals. The acetylcholine-induced renal artery dilation at baseline negatively correlated with lisinopril-induced reduction of proteinuria ( r2= 0.648, P = 0.003) and with the decrease in SBP ( r2= 0.592, P = 0.006). Our data suggest that angiotensin-converting enzyme-inhibitor attenuates the progression of renal damage the most in those individuals with decreased basal renal endothelial-mediated vasodilation.

Despite its advantages, discrete-trial instruction (DTI) has been criticized for producing rote responding. Although there is little research supporting this claim, if true, this may be problematic given the propensity of children with autism to engage in restricted and repetitive behavior. One feature that is common in DTI that may contribute to rote responding is the prompting and reinforcement of one correct response per discriminative stimulus. To evaluate the potential negative effects of rote prompts on varied responding, we compared the effects of modeling rote versus varied target responses during the teaching of intraverbal categorization. We also evaluated the effects of these procedures on the efficiency of acquisition of any one correct response. For all four children, any increase in varied responding was fleeting, and for two participants, acquisition was slower in the variable-modeling condition.

Extensive research has shown that the variability of organismal behavior is great when contingent reinforcement is delayed, small, or improbable. This research has generally employed stable response-reinforcer relationships, and therefore is limited in its explanatory scope with respect to a dynamic environment. We conducted two experiments to investigate whether pigeons' conditioned pecking behavior shows anticipatory or perseverative patterns of behavioral variability when the reinforcement probability reliably changes within experimental sessions. In Experiment 1, three pigeons received alternating sessions in which the reinforcement probability (35% or 4.2%) was shifted at the midpoint of each session in the presence of the same discrete cue. Experiment 2 featured a similar design, but with the inclusion of a discrete visual cue that changed at the session midpoint, and thus unambiguously indicated reinforcement probability. Local reinforcement rates only reliably controlled response variability when a discrete visual cue was available. Without this, pigeons did not discriminate between trial types in the first halves of sessions, and showed evidence of perseveration of response variability following a within-session shift. Critically, this is the first experimental demonstration that the relationship between reinforcement probability and behavioral variability is moderated by another factor (i.e., trial position within a session). This study thus expands our understanding of the control of behavioral variability as a function of experiential factors.

Purpose To study how noise and scanner response variability affect radiochromic film dosimetry. Methods Five treatment plans were analyzed in this work with two different multichannel protocols: the multichannel algorithm of Mayer et al. and the efficient protocol of Lewis et al. Results and conclusion The multichannel protocol of Mayer et al. is not able to compensate variability in scanner response, which is an important issue for radiochromic film dosimetry. The efficient protocol compensates variations of scanner response, so dose values and gamma scores become more accurate and reproducible. The compensation of digitizer scan variability of the efficient protocol, together with time averaging improve radiochromic film dosimetry. Noise is related to selected resolution in the scanner, our results show that if high resolution measurements are required, de-noising should be considered.

An enhanced and efficient methodology is proposed for evaluating the robustness of an uncertain structure with passive dampers. Although the structural performance for seismic loads is an important design criterion in earthquake-prone countries, the structural parameters such as storey stiffnesses and damping coefficients of passive dampers are uncertain due to various factors or sources, e.g. initial manufacturing errors, material deterioration, temperature dependence. The concept of robust building design under such uncertain structural-parameter environment may be one of the most challenging issues to be tackled recently. By applying the proposed method of interval analysis and robustness evaluation for predicting the response variability accurately, the robustness of a passively controlled structure can be evaluated efficiently in terms of the so-called robustness function. An application is presented of the robustness function to the design and evaluation of passive damper systems.

Human sensory processing is inherently noisy: if a participant is presented with the same set of stimuli multiple times and is asked to perform a task related to some property of the stimulus by pressing one of two buttons, the set of responses generated by the participant will differ on different presentations even though the set of stimuli remained the same. This response variability can be used to estimate the amount of internal noise (i.e. noise that is not present in the stimulus but in the participant’s decision making process). The procedure by which the same set of stimuli is presented twice is referred to as double-pass (DP) methodology. This procedure is well-established, but there is no accepted recipe for how the repeated trials may be delivered (e.g. in the same order as they were originally presented, or in a different order); more importantly, it is not known whether the choice of delivery matters to the resulting estimates. Our results show that this factor (as well as feedback) has no measurable impact. We conclude that, for the purpose of estimating internal noise using the DP method, the system can be assumed to have no inter-trial memory.

Background: Temporal summation of second pain (TSSP) is relevant for the study of central sensitization, and refers to increased pain evoked by repetitive stimuli at a constant intensity. While the literature reports on participants whose pain ratings increase with successive stimuli, response to a TSSP protocol can be variable. The aim of this study was to characterize the full range of responses to a TSSP protocol in pain-free adults. Method: Three hundred twelve adults received a train of brief, repetitive heat stimuli at a fixed temperature and rated the intensity of second pain after each pulse. TSSP response (D in pain ratings) was quantified using the most common methods in the literature, and response groups were formed: TSSP (D > 0), no change ( D= 0), and temporal decrease in second pain (TDSP) (D < 0). A cluster analysis was performed on the D values to empirically derive response groups. Results: Depending on how TSSP response was quantified, 61‐72% of the sample demonstrated TSSP, 11‐28% had no change in pain ratings and 0‐20% demonstrated TDSP. The cluster analysis found that the majority (59%) of participants fell in the no change cluster, 29% clustered into the TSSP group and 12% in the TDSP cluster. Conclusions: Using a fixed thermal paradigm, pain-free adults exhibit substantial variability in response to a TSSP protocol not well characterized by group-mean slopes. Studies are needed to determine TSSP response patterns in clinical samples, identify predictors of response and determine the clinical implications of response variability.

Greater accommodative lag and vergence deficits have been linked to attentional deficits similar to those observed in Attention Deficit Hyperactivity Disorder (ADHD). The purpose of the present study was to assess the effect of accommodative–vergence stress on a measure of sustained attention (Conners CPT) used in the diagnosis of ADHD. Twenty-seven normal non-ADHD adults completed the Conners CPT twice: wearing −2.00 D lenses and normally (without the −2.00 D lenses) in a counterbalanced order with at least 24h between the sessions. Simultaneous recording of participants’ dynamic accommodative responses was performed from the right eye using the Grand Seiko WAM-5500 auto-refractor and electroencephalographic activity (EEG) in the left prefrontal region using the Neurosky Mindset headset. The results demonstrated a significantly greater accommodative lag in the −2.00 D stress condition and a significantly poorer performance on the Conners CPT as indexed by slower reaction time, greater standard error of hit reaction time, grater response variability, poorer stimulus detectability and a greater number of perseverations. No differences were observed on measures of EEG in the theta (4–7Hz), alpha (8–12Hz), and beta (12–20Hz) bands. Moreover, when directly juxtaposed with each EEG band in multiple linear regression analyses, greater accommodative lag in the stress condition was significantly associated with a greater probability of clinical classification on the Conners CPT, and was also marginally predictive of the number of omissions recorded in the stress condition. The results demonstrated that sustained attention can be influenced by such factors as accommodative–vergence stress and suggest that bottom-up processes can contribute to and potentially exacerbate attentional problems in individuals with ADHD. The study also showed that cortical dysfunction (while sufficient) may not be a necessary condition for attentional deficits.

While it is well established that humans respond to inequity, it remains unclear the extent to which this behavior occurs in our non-human primate relatives. By comparing a variety of species, spanning from New World and Old World monkeys to great apes, scientists can begin to answer questions about how the response to inequity evolved, what the function of this response is, and why and how different contexts shape it. In particular, research across non-human primate species suggests that the response is quite variable across species, contexts, and individuals. In this paper, we aim to review these differences in an attempt to identify and better understand the patterns that emerge from the existing data with the goal of developing directions for future research. To begin, we address the importance of considering socio-ecological factors in non-human primates in order to better understand and predict expected patterns of cooperation and aversion to inequity in different species, following which we provide a detailed analysis of the patterns uncovered by these comparisons. Ultimately, we use this synthesis to propose new ideas for research to better understand this response and, hence, the evolution of our own responses to inequity.

Research has shown that variability may be an operant dimension of behavior. One method of reinforcing response variability is to use a lag schedule of reinforcement (Page & Neuringer, 1985). Several studies have shown that a Lag 1 schedule is effective in increasing variable responding with human participants (e.g., Esch, Esch, & Love, 2009; Lee, McComas, & Jawor, 2002). In these arrangements, however, the return to baseline responding during reversal phases suggests that the resulting behavior change may not be maintained following intervention. The purpose of the present study was to investigate the effects of a Lag 3 schedule on increasing and maintaining variability of tacts in 2 children diagnosed with developmental disabilities. Results demonstrated increased variability in tacting for both participants and maintenance in variable responding after a 3-week follow-up.

Background A study was completed to assess the academic and state-level professional optometry leadership views regarding optometry professionals as surge responders in the event of a catastrophic event. Methods A cross-sectional survey was conducted using a 21-question, self-administered, structured questionnaire. All U.S. optometry school deans and state optometric association presidents were mailed a questionnaire and instructions to return it by mail on completion; 2 repeated mailings were made. Descriptive statistics were produced and differences between deans and association presidents were tested by Fisher exact test. Results The questionnaire response rate was 50% (25 returned/50 sent) for the state association presidents and 65% (11/17) for the deans. There were no statistically significant differences between the leadership groups for any survey questions. All agreed that optometrists have the skills, are ethically obligated to help, and that optometrists should receive additional training for participation in disaster response. There was general agreement that optometrists should provide first-aid, obtain medical histories, triage, maintain infection control, manage a point of distribution, prescribe medications, and counsel the “worried well.” Starting intravenous lines, interpreting radiographs, and suturing were less favorably supported. There was some response variability between the 2 leadership groups regarding potential sources for training. Conclusions The overall opinion of optometry professional leadership is that with additional training, optometrists can and should provide an important reserve pool of catastrophic event responders.

Objective Slow and variable reaction times (RTs) on fast tasks are such a prominent feature of attention-deficit/hyperactivity disorder (ADHD) that any theory must account for them. However, this has proven difficult because the cognitive mechanisms responsible for this effect remain unexplained. Although speed and variability are typically correlated, it is unclear whether single or multiple mechanisms are responsible for group differences in each. RTs are a result of several semi-independent processes, including stimulus encoding, rate of information processing, speed-accuracy trade-offs, and motor response, which have not been previously well characterized. Method A diffusion model was applied to RTs from a forced-choice RT paradigm in two large, independent case-control samples (NCohort 1 = 214 and NCohort 2 = 172). The decomposition measured three validated parameters that account for the full RT distribution and assessed reproducibility of ADHD effects. Results In both samples, group differences in traditional RT variables were explained by slow information processing speed, and unrelated to speed-accuracy trade-offs or nondecisional processes (e.g., encoding, motor response). Conclusions RT speed and variability in ADHD may be explained by a single information processing parameter, potentially simplifying explanations that assume different mechanisms are required to account for group differences in the mean and variability of RTs.

Interindividual variability in the pharmacological response to antiplatelet drugs has been reported in some studies. Suboptimal response to aspirin, as determined by specific tests (serum thromboxane B2), appears to be rare and in most cases is caused by poor compliance. In contrast, studies using specific tests to measure the pharmacological effect of clopidogrel showed a wide variability of responses, with a significant number of subjects (approximately one-third) who were very poor responders. Interindividual differences in the extent of metabolism of clopidogrel to its active metabolite is the most plausible mechanism for the observed interindividual variability in platelet inhibition. Tailored treatment based on laboratory monitoring of platelet function has been proposed as a solution to poor responsiveness to clopidogrel. However, we still need to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness before monitoring clopidogrel therapy can be recommended in clinical practice.

Objective: Patients with ADHD are typically more variable in their reaction times (RT) than control children. Signal processing analyses have shown that time series RT data of children with ADHD have a distinctive low frequency periodic structure suggestive of a pattern of occasional spontaneous performance lapses. Here we use a fine-grained analysis of spectral power across a broader frequency range to differentiate the periodic qualities of ADHD time series RT data from (a) 1/frequency noise, and (b) control performance. We also assess the familiality of these frequencies by using a proband-sibling design. Method: Seventy-one children with ADHD, one of their siblings, and 50 control participants completed a simple RT task. Power across the RT frequency spectrum was calculated. The frequencies significantly differentiating the two groups were identified. Familiality was assessed in two ways: first, by comparing probands with their unaffected siblings and controls, and, second, by investigating the siblings of neuropsychologically impaired and unimpaired children with ADHD. Results: Analyses converged to highlight the potential importance of the .20–.26 Hz band in differentiating the periodic structure of ADHD RT time series data from both 1/frequency noise and control performance. This frequency band also showed the strongest evidence of familiality. Conclusions: RT performance of children with ADHD had a distinctive periodic structure. The band identified as most differentiating and familial was at a higher frequency than in most previous reports. This highlights the importance of employing tasks with faster interstimulus intervals that will allow a larger portion of the frequency spectrum to be examined. (PsycINFO Database Record (c) 2011 APA, all rights reserved)

To improve the quality of prosthetic vision, it is important to understand how retinal neurons respond to electric stimulation. Previous studies present conflicting reports as to the maximum rate at which retinal ganglion cells can “follow” pulse trains, i.e., generate one spike for each pulse of the train. In the present study, we measured the response of 5 different types of rabbit retinal ganglion cells to pulse trains of 100–700 Hz. Surprisingly, we found significant heterogeneity in the ability of different types to follow pulse trains. For example, brisk transient (BT) ganglion cells could reliably follow pulse rates up to 600 pulses per second (PPS). In contrast, other types could not even follow rates of 200 PPS. There was additional heterogeneity in the response patterns across those types that could not follow high-rate trains. For example, some types generated action potentials in response to approximately every other pulse, whereas other types generated one spike per pulse for a few consecutive pulses and then did not generate any spikes in response to the next few pulses. Interestingly, in the types that could not follow high-rate trains, we found a second type of response: many pulses of the train elicited a biphasic waveform with an amplitude much smaller than that of standard action potentials. This small waveform was often observed following every pulse for which a standard spike was not elicited. A possible origin of the small waveform and its implication for effective retinal stimulation are discussed.

Delayed reward discounting (DRD) is a common index of impulsivity that refers to an individual's devaluation of rewards based on delay of receipt and has been linked to alcohol misuse and other maladaptive behaviors. The current study investigated response consistency and reward magnitude effects in two measures of DRD in a sample of 111 undergraduates who consumed an average of 10.7 drinks/week. These variables were also examined in relation to alcohol use and misuse. Results indicated highly consistent performance on both measures of DRD, although significant differences were evident based on task parameters. There was also clear evidence of a magnitude effect on DRD. Finally, a number of significant associations between DRD and both alcohol use and misuse were found. These findings suggest that individuals possess a relatively consistent cognitive template for DRD choice preferences, but that the template systematically varies by both reward magnitude and delay length.

Objectives: This study sought to determine whether the pharmacokinetic (PK) and pharmacodynamic (PD) responses to high or standard clopidogrel loading doses (LDs) differ according to CYP2C19*2 alle...

The Script Concordance Test (SCT) uses a panel-based, aggregate scoring method that aims to capture the variability of responses of experienced practitioners to particular clinical situations. The use of this type of scoring method is a key determinant of the tool’s discriminatory power, but deviant answers could potentially diminish the reliability of scores by introducing measurement error. (1) to investigate the effects on SCT psychometrics of excluding from the test’s scoring key either deviant panelists or deviant answers; (2) to propose a method for excluding either deviant panelists or deviant answers. Using an SCT in radiation oncology, we examined three methods for reducing panel response variability. One method (‘outliers’) entailed removing from the panel members with very low total scores. Two other methods (‘distance-from-mode’ and ‘judgment-by-experts’) excluded widely deviant responses to individual questions from the test’s scoring key. We compared the effects of these methods on score reliability, correlations between original and adjusted scores, and between-group effect sizes (panel-residents; panel-students; and residents-students). With a large panel (n = 45), optimization methods have no effect on reliability of scores, correlation and effect size. With a smaller panel (n = 15) no significant effect of optimization methods were observed on reliability and correlation, but significant variation on effect size was observed across samples. Measurement error resulting from deviant panelist responses on SCTs is negligible, provided the panel size is sufficiently large (>15). However, if removal of deviant answers is judged necessary, the distance-from-mode strategy is recommended.

BackgroundTwin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ.MethodMultivariate familial models were run on data from 1265 individuals aged 6–18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice–delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI).ResultsSignificant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41–0.71) and IQ (rF=−0.25 to −0.49). The association between ADHD and cognitive performance was largely independent (80–87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ.ConclusionsThe aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

SummaryInterindividual response variability to clopidogrel treatment is a well established phenomenon. In recent studies and ongoing large-scale trials where patients with high on-treatment platelet reactivity (HPR) to clopidogrel are being randomised to an intensified antiplatelet treatment, confirmation of the HPR phenotype is based on one single platelet function assessment. The stability of the HPR phenotype over time has never been investigated but should be considered crucial for justification of intensified antiplatelet treatment regimens beyond clinical trials. The goal of this study was to test for the stability of the HPR phenotype over time in clopidogrel-treated patients. Patients (n=31) under chronic clopidogrel treatment (75 mg/day) were investigated by serial adenosine diphosphate (ADP)-induced platelet aggregation assessment with multiple electrode aggregometry (MEA) on a Multiplate analyser and light transmission aggregometry (LTA) at three different time points (once per week) during monitored antiplatelet treatment. On the basis of a cut-off level approach (468 AU*min for MEA, 53% for LTA) patients were classified into patients with (n=27) or without (n=4) HPR. For MEA, the phenotype was stable in 93.5% (n=29) of patients whereas 6.5% (n=2) crossed the cut-off level. For LTA, the phenotype was stable in 68% (n=21) of patients whereas 32% (n=10) patients crossed the cut-off level (chi-square P=0.01 for comparison of pheno-type stability between both assays). In conclusion, the HPR phenotype is stable over time in the majority of clopidogrel-treated patients. Comparative assessment of phenotype stability across available platelet function assays warrants further investigation.

Resume Le trouble bipolaire (TB) est un trouble severe de l’humeur (2 % de la population generale, sixieme cause de handicap, 50 % des cas avant 21 ans) caracterise par un taux eleve de recurrences (70 a 80 % de rechutes en moyenne a deux ans et malgre le traitement). Le lithium est le traitement de reference pour la prevention de ces rechutes. L’evaluation de cette efficacite prophylactique (espacement et diminution de l’intensite des rechutes) necessite plusieurs annees de traitement continu (au minimum deux ans). Quarante pour cent des patients traites par lithium n’ont pas un cours evolutif ameliore de la maladie, ce qui pourrait etre lie a des connaissances insuffisantes concernant la forme retard (Li LP) essentiellement utilisee : (i) aucune etude pharmacocinetique (PK) de l’adulte, du lithium plasmatique n’est disponible pour le Li LP dont la fourchette therapeutique (mesuree a 12 heures) est fondee sur des correspondances approximatives avec les lithiemies cibles du lithium a liberation immediate (taux residuel), (ii) aucune etude pharmacodynamique (PD) contributive (efficacite prophylactique) n’a permis de valider la fourchette therapeutique utilisee en pratique courante. Les mecanismes de transport du Li au travers de la barriere hemato-encephalique (BHE) sont le siege de regulations qui sont mal connues mais il existe des arguments qui suggerent fortement une plasticite de cette derniere sous l’influence du Li. Dans cet article, nous passons en revue les developpements necessaires de la recherche qui permettront de mieux comprendre les mecanismes qui sous-tendent cette variabilite de la reponse au lithium.

Two experiments evaluated history effects on induced and operant variability. College students typed three-digit sequences on a computer keyboard. Sequence variability was induced (by no reinforcement or variation- independent reinforcement) or reinforced (by variation- or repetition-dependent reinforcement). Conditions with induced and operant variability were presented according to a reverse between-groups design. In Experiment 1, we examined transitions from the variation or repetition contingencies to no reinforcement, and vice versa. In Experiment 2, the variation or repetition contingencies were followed or preceded by variation-independent reinforcement. The results showed that (1) a history of no reinforcement impaired operant variability learning; (2) induced variability levels were higher and lower after a history of reinforcement for variation and repetition, respectively; (3) repetition was more easily disrupted by no reinforcement and independent reinforcement than was variation; and (4) response variability and stability were a function of past and current reinforcement conditions. These results indicate that reinforcement history influences both induced and operant variability levels.

Sensory neurons represent stimulus information with sequences of action potentials that differ across repeated measurements. This variability limits the information that can be extracted from momentary observations of a neuron's response. It is often assumed that integrating responses over time mitigates this limitation. However, temporal response correlations can reduce the benefits of temporal integration. We examined responses of individual orientation-selective neurons in the primary visual cortex of two macaque monkeys performing an orientation-discrimination task. The signal-to-noise ratio of temporally integrated responses increased for durations up to a few hundred milliseconds but saturated for longer durations. This was true even when cells exhibited little or no adaptation in their response levels. These observations are well explained by a statistical response model in which spikes arise from a Poisson process whose stimulus-dependent rate is modulated by slow, stimulus-independent fluctuations in gain. The response variability arising from the Poisson process is reduced by temporal integration, but the slow modulatory nature of variability due to gain fluctuations is not. Slow gain fluctuations therefore impose a fundamental limit on the benefits of temporal integration.

Current available data show that about 5 to 40% of coronary patients treated with conventional doses of antithrombotic drugs do not display adequate antiplatelet response. Nowadays, aspirin remains the main antiplatelet therapy. However, a significant number of patients show platelet resistance to aspirin therapy, and recurrent thrombotic events occur. Combined antithrombotic therapies with thienopyridines, such as clopidogrel have been used to resolve this problem. However, clopidogrel treatment has been also associated with wide response variability, and non-responsiveness to clopidogrel also occurs in some patients. Therefore, the main question arising about the antithrombotic therapy is why particular patients do not benefit from the therapy and how they might be identified to improve their treatment. Different hypotheses have been suggested, including genetic factors, platelet heterogeneity, non-compliance and others. However, it is probably that many molecular mechanisms involved in platelet resistance to antithrombotic therapies still remains unknown. New technologies, such as proteomics and genetic, are beginning to show new unknown biological biomarkers and molecular mechanisms which may be associated with platelet antithrombotic drug resistance.

BackgroundAttention deficit hyperactivity disorder (ADHD) shows a strong phenotypic and genetic association with reaction time (RT) variability, considered to reflect lapses in attention. Yet we know little about whether this aetiological pathway is shared with other affected cognitive processes in ADHD, such as lower IQs or the generally slower responses (mean RTs). We aimed to address the question of whether a shared set of genes exist that influence RT variability, mean RT, IQ and ADHD symptom scores, or whether there is evidence of separate aetiological pathways.MethodMultivariate structural equation modelling on cognitive tasks data (providing RT data), IQ and ADHD ratings by parents and teachers collected on general population sample of 1314 twins, at ages 7–10 years.ResultsMultivariate structural equation models indicated that the shared genetic influences underlying both ADHD symptom scores and RT variability are also shared with those underlying mean RT, with both types of RT data largely indexing the same underlying liability. By contrast, the shared genetic influences on ADHD symptom scores and RT variability (or mean RT) are largely independent of the genetic influences that ADHD symptom scores share with IQ.ConclusionsThe finding of unique aetiological pathways between IQ and RT data, but shared components between mean RT, RT variability and ADHD symptom scores, illustrates key influences in the genetic architecture of the cognitive and energetic processes that underlie the behavioural symptoms of ADHD. In addition, the multivariate genetic model fitting findings provide valuable information for future molecular genetic analyses.

Prescribers have been practicing stratified medicine for many years. Patient characteristics, usually non-genetic, including age, comorbidities and concomitant medications are taken into account when deciding which drug to prescribe. In addition, the majority of drugs require dose adjustments across patient subgroups, usually determined by non-genetic differences between the subgroups. Whilst pharmacogenetics hold promise for enhancing treatment stratification and even treatment individualisation, non-genetic factors will continue to be very important. Both non-genetic and genetic factors must be considered to improve understanding and quantification of the variability in treatment outcomes and to guide stratification and targeting of patient subgroups to the right drug and also to the right range of doses within that subgroup. Development of stratified medicines must consider non-genetic as well as genetic factors and, where appropriate, include stratification through optimising the dose for each patient or subgroup as well as by choosing the drug most likely to deliver efficacy to that patient or group.

International audience; The paper is focused on a sensitivity analysis developed to study the relevance of experimental hardening curves obtained from tube bulging test to quantify the influence and the contribution of experimental uncertainties on the response variability. The experiments are based on “online” measurements of the internal pressure and the bulge height. A semi analytical model developed from a geometrical representation of the bulged tube and equilibrium of infinitesimal volumes (slab method) permits to evaluate the stress-strain curve. The differentiation of all the equations of the model and the evaluation of all the input parameters allow to get the total uncertainty on the resulting hardening curve and to identify the critical experimental parameters. Hence the results of this sensitivity analysis open up ways of improvements for conducting experimental tube bulging test.

Humans and lower animals time as if using an internal clock that can be “stopped” or “reset” on command (reviewed by Buhusi & Meck, 2005). The internal clock concept assumes that pulses emitted by a pacemaker are stored in an accumulator whose content represents the current subjective time (Fraisse, 1957; Francois, 1927; Hoagland, 1933; Treisman, 1963; Woodrow, 1930). A case in point that the internal clock can be used in discrete (stop/reset) modes is given by the response pattern in the peak-interval (PI) procedure with gaps, or PI-GAP procedure (Church, 1978; S. Roberts, 1981) (Figure 1). In the standard version of this procedure, during fixed-interval (FI) trials, the first response after a specified criterion, say 30 s, from the onset of a to-be-timed signal is reinforced (Figure 1A). In PI trials, the to-be-timed signal is presented but subject’s responses are not reinforced; typically, in PI trials the average response rate increases after the onset of the to-be-timed signal, reaches a peak about the time when subjects’ responses were (sometimes) reinforced, and declines afterwards (Catania, 1970; Church, 1978) (Figure 1A). During gap trials, a brief interruption (gap) of the to-be-timed signal prompts a delay in response relative to PI trials by about the duration of the gap, suggesting that on average subjects retain in working memory the pre-gap interval and resume timing after the gap where they left off before the gap, a response mode (alternative) called stop (e.g., Church, 1978; S. Roberts & Church, 1978) (Figure 1A). However, a quite different response pattern is observed in the reversed version of the PI procedure (Buhusi & Meck, 2000), in which subjects time the absence of a signal (e.g., in the dark) and their timing is interrupted by a signaled (e.g., illuminated) gap (Figure 1B): Subjects delay their response function after the gap for a duration that is approximately the sum of the gap and pre-gap intervals, suggesting that on average they restart the entire timing process after the gap, using a reset response (Buhusi & Meck, 2000). Figure 1 The peak-interval (PI) procedure with gaps Because the results presented in Figure 1 were obtained by averaging response rate over many trials, there is the possibility that the stop / reset modes represent averaging artifacts that do not readily reflect the behavior of the subjects in the experimental box. Indeed, while the average response function in PI trials is Gaussian-like (Figure 1), during individual PI trials both pigeons (Cheng & Westwood, 1993) and rats (Church, Meck, & Gibbon, 1994; Gibbon & Church, 1990) use a low-high-low pattern of response (Figure 2B). Similarly, during individual gap trials the pattern of response is relatively complex: Some gap trials follow a low-high-low-high-low pattern, while some lack pre-gap responses altogether, and have a pattern similar to that from PI trials, but delayed. Such complex response patterns challenge current interval timing theories, developed to address data averaged over many trials (e.g., Gibbon, Church, & Meck, 1984). To address the complex behavior in the PI-GAP procedure, two classes of theoretical interpretations have been proposed, attributing response variability to either the internal clock or to the interaction between the internal clock and other cognitive processes: Initial investigations indicated that on average rodents tend to stop (e.g., Church, 1978; S. Roberts & Church, 1978), while birds tend to reset (Bateson & Kacelnik, 1998; Brodbeck, Hampton, & Cheng, 1998; Cabeza de Vaca, Brown, & Hemmes, 1994; W. A. Roberts, Cheng, & Cohen, 1989), suggesting that the stop/reset response alternatives reflect discrete modes of the internal clock (Church, 1978), accounted for by a switch connecting the pacemaker and the accumulator, allowing or not pulse accumulation (Church, 1978; Gibbon et al., 1984). Figure 2 Example of singe-trial statistics distributions and for an individual subject In contrast, recent results indicate that rats reset their timing in PI trials upon presentation of reinforcement (Matell & Meck, 1999; Thorpe, Petrovic, & Wilkie, 2002), that both rats and pigeons stop or reset depending on gap content (Buhusi & Meck, 2000), gap discriminability (Buhusi, Perera, & Meck, 2005), gap/signal contrast (Buhusi & Cerutti, 2005; Buhusi, Sasaki, & Meck, 2002), and subjects’ visual acuity (Buhusi et al., 2005), and that similar delays are obtained when the procedure includes distracter events rather than gaps (Buhusi & Meck, 2006a, 2006b). These departures from the stop/reset modes support the alternative interpretation that the average response after a gap does not reflect discrete modes of the internal clock, but rather that working memory for time is sensitive to Resource Allocation (RA) (Buhusi, 2003), a process external to the clock, actively controlled by the perceived salience of events. This interpretation accounts not only for the discrete stop and reset responses, but also for a continuum of responses in between stop and reset. Here we evaluate whether the pattern of response in individual gap trials is consistent with either discrete modes of the internal clock (Gibbon et al., 1984) or a continuum of alternatives (Buhusi, 2003). To reconcile these views, Cabeza de Vaca et al. (1994) proposed a “stochastic” model, denoted here as the Probability-of-Reset hypothesis (PR), which assumes that during individual gap trials subjects use discrete alternatives (stop / reset) with a certain probability, such that the average response functions in gap trials is a mix of the “stop and “reset” responses, thus falling in between stop and reset, and giving the appearance of a continuous range of alternatives. This distinction is lost when analyzing average response functions, and requires special individual-trial analyses. Evidence for the PR hypothesis was previously sought by Cabeza de Vaca et al. (1994), by estimating the time of response initiation S1 (“start”) and the time of response termination S2 (“stop”) for each individual trial using Gibbon & Church’s (1990) algorithm (Figure 3A). Acknowledging that applying this algorithm to gap trials is problematic because they do not have a consistent start-stop pattern (Figure 2B), Cabeza de Vaca et al. focused on the stop time S2, which is reliably identified by the algorithm irrespective of trial type (PI or gap). Because the PR hypothesis assumes that subjects stochastically use stop and reset alternatives in gap trials, it predicts that the distributions of individual-trial statistics (e.g., S2) should be bi-modal in gap trials and wider in gap trials relative to PI trials (Cabeza de Vaca et al., 1994). However, analyses of pigeon’s responses failed to indicate bi-modality of S2 distribution in gap trials. Nevertheless, the S2 distribution was found to be wider for late gaps than for early gaps, thus providing partial support the PR hypothesis (Cabeza de Vaca et al., 1994). Figure 3 Single-trial analysis of the response pattern in the PI procedure with gaps The mixed results obtained Cabeza de Vaca et al. (1994) may be equally due to the algorithm used (Church et al., 1994; Gibbon & Church, 1990), since gap trials do not follow a consistent start-stop pattern, but also due to the species investigated, since pigeons have a known tendency to reset (W. A. Roberts et al., 1989) and are possibly less prone to stochastic variations in their responses. Therefore, here we extended the Church & Gibbon (1990) algorithm to gap trials with multiple start-stops (Figure 3B), and we applied this new algorithm to the analysis of rat’s response pattern in individual gap trials in the standard and reversed PI-GAP procedure (Buhusi & Meck, 2000) to evaluate the predictions of the PR hypothesis. Finally, we evaluated how well the PR and RA hypotheses fit the observed distributions of start and stop times in individual trials by computing an index of superposition (intra-class correlation, ICC) between observed and hypothetical distributions. By evaluating response variability as predicted by PR – an account relying on discrete modes of the internal clock – and by RA – an account based on the continuum of interactions between the internal clock and other cognitive processes, our study speaks more generally about the complex cognitive processes at work in behavioral tasks involving interval timing.

In 2 studies, we investigated age effects in the ability to recognize dynamic posed and spontaneous smiles. Study 1 showed that both young and older adult participants were above chance in their ability to distinguish between posed and spontaneous smiles in young adults. In Study 2, we found that young adult participant performance declined when judging a combination of both young and older adult target smiles, while older adult participants outperformed young adult participants in distinguishing between posed and spontaneous smiles. A synthesis of results across the 2 studies showed a small-to-medium age effect (d = -0.40), suggesting that older adults have an advantage in discriminating between smile types. Mixed stimuli (i.e., a mixture of young and older adult faces) may impact accurate smile discrimination. In future research, both the sources (cues) and behavioral effects of age-related differences in the discrimination of positive expressions should be investigated.

Oral antiplatelet therapy with clopidogrel and aspirin is an important and widely prescribed strategy to prevent ischemic events in patients with cardiovascular diseases. However, the occurrence of thrombotic events including stent thrombosis is still high (10%). Current practice guidelines are mainly based on large-scale trials focusing on clinical endpoints and 'one size fits all' strategies of treating all patients with the same clopidogrel doses. Pharmacodynamic studies have demonstrated that the latter strategy is associated with wide response variability where a substantial percentage of patients show nonresponsivenes. Translational research studies have established the relation between clopidogrel nonresponsivenes or high on-treatment platelet reactivity to adverse clinical events, thereby establishing clopidogrel nonresponsivenes as an important emerging clinical entity. Clopidogrel response variability is primarily a pharmacokinetic phenomenon associated with insufficient active metabolite generation that is secondary to i) limited intestinal absorption affected by an ABCB1 gene polymorphism; ii) functional variability in P450 isoenzyme activity; and iii) a genetic polymorphism of CYP450 isoenzymes. Personalized antiplatelet treatment with higher clopidogrel doses in selected patients or with newer more potent P2Y(12) receptor blockers based on individual platelet function measurement can overcome some of the limitations of current clopidogrel treatment.

Deficits in sustained attention may represent an endophenotype for bipolar disorder (BD). One heritable measure of sustained attention is intrasubject variability in response time (ISV-RT). We tested the hypothesis that, compared with controls, both youths with BD and those at familial risk for the disorder would have increased ISV-RT.Subjects were 28 patients with BD, 26 unaffected youths with a first-degree relative with BD, and 24 control youths without an affected relative, all aged 7 to 17 years. Subjects completed the Flanker Continuous Performance Test.Bipolar disorder and at-risk youths had increased ISV-RT, compared with the controls. Differences were independent of comorbid psychopathology in youths with BD and present in psychiatrically healthy at-risk youths.Increased ISV-RT may be a risk marker for BD. Further research is needed to investigate the neural and genetic underpinnings of this deficit, as well as the specificity of the finding to BD.