Conditional deviant repetition in the oddball paradigm modulates processing at the level of P3a but not MMN.

The auditory system has an amazing ability to rapidly encode auditory regularities. Evidence comes from the popular oddball paradigm, in which frequent (standard) sounds are occasionally exchanged for rare deviant sounds, which then elicit signs of prediction error based on their unexpectedness (e.g., MMN and P3a). Here, we examine the widely neglected characteristics of deviants being bearers of predictive information themselves; naive participants listened to sound sequences constructed according to a new, modified version of the oddball paradigm including two types of deviants that followed diametrically opposed rules: one deviant sound occurred mostly in pairs (repetition rule), the other deviant sound occurred mostly in isolation (non-repetition rule). Due to this manipulation, the sound following a first deviant (either the same deviant or a standard) was either predictable or unpredictable based on its conditional probability associated with the preceding deviant sound. Our behavioral results from an active deviant detection task replicate previous findings that deviant repetition rules (based on conditional probability) can be extracted when behaviorally relevant. Our electrophysiological findings obtained in a passive listening setting indicate that conditional probability also translates into differential processing at the P3a level. However, MMN was confined to global deviants and was not sensitive to conditional probability. This suggests that higher-level processing concerned with stimulus selection and/or evaluation (reflected in P3a) but not lower-level sensory processing (reflected in MMN) considers rarely encountered rules.

New IPECAD open-source model framework for the health technology assessment of early Alzheimer's disease treatment: development and use cases.

OBJECTIVES: Reimbursement decisions for new Alzheimer's disease (AD) treatments are informed by economic evaluations. An open-source model with intuitive structure for model cross-validation can support the transparency and credibility of such evaluations. We describe the new IPECAD open-source model framework (version 2) for the health-economic evaluation of early AD treatment and use it for cross-validation and addressing uncertainty. METHODS: A cohort state transition model using a categorized composite domain (cognition and function) was developed by replicating an existing reference model and testing it for internal validity. Then, features of existing "ICER" and "AD-ACE" models assessing lecanemab treatment were implemented for model cross-validation. Additional uncertainty scenarios were performed on choice of efficacy outcome from trial, natural disease progression, treatment effect waning and stopping rules, and other methodological choices. The model is available open-source as R code, spreadsheet and web-based version via https://github.com/ronhandels/IPECAD. RESULTS: In the IPECAD model incremental life years, QALY gains and cost savings were 21-31% smaller compared to the ICER model and 36-56% smaller compared to the AD-ACE model. IPECAD model results were particularly sensitive to assumptions on treatment effect waning and stopping rules and choice of efficacy outcome from trial. CONCLUSIONS: We demonstrated the ability of a new IPECAD opens-source model framework for researchers and decision-makers to cross-validate other (HTA submission) models and perform additional uncertainty analyses, setting an example for open science in AD decision modeling and supporting important reimbursement decisions.

Attention deployment in natural scenes: Higher-order scene statistics rather than semantics modulate the N2pc component.

Which properties of a natural scene affect visual search? We consider the alternative hypotheses that low-level statistics, higher-level statistics, semantics, or layout affect search difficulty in natural scenes. Across three experiments (n = 20 each), we used four different backgrounds that preserve distinct scene properties: (a) natural scenes (all experiments); (b) 1/f noise (pink noise, which preserves only low-level statistics and was used in Experiments 1 and 2); (c) textures that preserve low-level and higher-level statistics but not semantics or layout (Experiments 2 and 3); and (d) inverted (upside-down) scenes that preserve statistics and semantics but not layout (Experiment 2). We included "split scenes" that contained different backgrounds left and right of the midline (Experiment 1, natural/noise; Experiment 3, natural/texture). Participants searched for a Gabor patch that occurred at one of six locations (all experiments). Reaction times were faster for targets on noise and slower on inverted images, compared to natural scenes and textures. The N2pc component of the event-related potential, a marker of attentional selection, had a shorter latency and a higher amplitude for targets in noise than for all other backgrounds. The background contralateral to the target had an effect similar to that on the target side: noise led to faster reactions and shorter N2pc latencies than natural scenes, although we observed no difference in N2pc amplitude. There were no interactions between the target side and the non-target side. Together, this shows that-at least when searching simple targets without own semantic content-natural scenes are more effective distractors than noise and that this results from higher-order statistics rather than from semantics or layout.

Perceptual learning of random acoustic patterns: Impact of temporal regularity and attention.

Perceptual learning is a powerful mechanism to enhance perceptual abilities and to form robust memory representations of previously unfamiliar sounds. Memory formation through repeated exposure takes place even for random and complex acoustic patterns devoid of semantic content. The current study sought to scrutinise how perceptual learning of random acoustic patterns is shaped by two potential modulators: temporal regularity of pattern repetition and listeners' attention. To this end, we adapted an established implicit learning paradigm and presented short acoustic sequences that could contain embedded repetitions of a certain sound segment (i.e., pattern) or not. During each experimental block, one repeating pattern recurred across multiple trials, whereas the other patterns were presented in only one trial. During the presentation of sound sequences that contained either temporally regular or jittered within-trial pattern repetitions, participants' attention was directed either towards or away from the auditory stimulation. Overall, we found a memory-related modulation of the event-related potential (ERP) and an increase in inter-trial phase coherence for patterns that recurred across multiple trials (compared to non-recurring patterns), accompanied by a performance increase in a (within-trial) repetition detection task when listeners attended the sounds. Remarkably, we show a memory-related ERP effect even for the first pattern occurrence per sequence when participants attended the sounds, but not when they were engaged in a visual distractor task. These findings suggest that learning of unfamiliar sound patterns is robust against temporal irregularity and inattention, but attention facilitates access to established memory representations upon first occurrence within a sequence.

Consolidated Health Economic Evaluation Reporting Standards - Value of Information (CHEERS-VOI): Explanation and Elaboration.

OBJECTIVES: Although the ISPOR Value of Information (VOI) Task Force's reports outline VOI concepts and provide good-practice recommendations, there is no guidance for reporting VOI analyses. VOI analyses are usually performed alongside economic evaluations for which the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 Statement provides reporting guidelines. Thus, we developed the CHEERS-VOI checklist to provide reporting guidance and checklist to support the transparent, reproducible, and high-quality reporting of VOI analyses. METHODS: A comprehensive literature review generated a list of 26 candidate reporting items. These candidate items underwent a Delphi procedure with Delphi participants through 3 survey rounds. Participants rated each item on a 9-point Likert scale to indicate its relevance when reporting the minimal, essential information about VOI methods and provided comments. The Delphi results were reviewed at 2-day consensus meetings and the checklist was finalized using anonymous voting. RESULTS: We had 30, 25, and 24 Delphi respondents in rounds 1, 2, and 3, respectively. After incorporating revisions recommended by the Delphi participants, all 26 candidate items proceeded to the 2-day consensus meetings. The final CHEERS-VOI checklist includes all CHEERS items, but 7 items require elaboration when reporting VOI. Further, 6 new items were added to report information relevant only to VOI (eg, VOI methods applied). CONCLUSIONS: The CHEERS-VOI checklist should be used when a VOI analysis is performed alongside economic evaluations. The CHEERS-VOI checklist will help decision makers, analysts and peer reviewers in the assessment and interpretation of VOI analyses and thereby increase transparency and rigor in decision making.

The value of maintaining cognition in patients with mild cognitive impairment: The innovation headroom and potential cost-effectiveness of roflumilast.

INTRODUCTION: Early health-technology assessment can support discussing scarce resource allocation among stakeholders. We explored the value of maintaining cognition in patients with mild cognitive impairment (MCI) by estimating: (1) the innovation headroom and (2) the potential cost effectiveness of roflumilast treatment in this population. METHODS: The innovation headroom was operationalized by a fictive 100% efficacious treatment effect, and the roflumilast effect on memory word learning test was assumed to be associated with 7% relative risk reduction of dementia onset. Both were compared to Dutch setting usual care using the adapted International Pharmaco-Economic Collaboration on Alzheimer's Disease (IPECAD) open-source model. RESULTS: The total innovation headroom expressed as net health benefit was 4.2 (95% bootstrap interval: 2.9-5.7) quality-adjusted life years (QALYs). The potential cost effectiveness of roflumilast was k€34 per QALY. DISCUSSION: The innovation headroom in MCI is substantial. Although the potential cost effectiveness of roflumilast treatment is uncertain, further research on its effect on dementia onset is likely valuable.

Neural signatures of temporal regularity and recurring patterns in random tonal sound sequences.

The auditory system is highly sensitive to recurring patterns in the acoustic input - even in otherwise unstructured material, such as white noise or random tonal sequences. Electroencephalography (EEG) research revealed a characteristic negative potential to periodically recurring auditory patterns - a response, which has been interpreted as memory trace-related and specific, rather than as a sign of periodicity-driven entrainment. Here, we aim to disentangle these two possible contributions by investigating the influence of a periodic sound sequence's inherent temporal regularity on event-related potentials. Participants were presented continuous sequences of short tones of random pitch, with some sequences containing a recurring pattern, and asked to indicate whether they heard a repetition. Patterns were either spaced equally across the random sequence (isochronous condition) or with a temporal jitter (jittered condition), which enabled us to differentiate between event-related potentials (and thus processing operations associated with a memory trace for a repeated pattern) and the periodic nature of the repetitions. A negative recurrence-related component could be observed independently of temporal regularity, was pattern-specific, and modulated by across trial repetition of the pattern. Critically, isochronous pattern repetition induced an additional early periodicity-related positive component, which started to build up already before the pattern onset and which was elicited undampedly even when the repeated pattern was occasionally not presented. This positive component likely reflects a sensory driven entrainment process that could be the foundation of a behavioural benefit in detecting temporally regular repetitions.

Optimizing the Use of High-Sensitivity Troponin Assays for the Early Rule-out of Myocardial Infarction in Patients Presenting with Chest Pain: A Systematic Review.

BACKGROUND: We assessed the accuracy and clinical effectiveness of high-sensitivity cardiac troponin (hs-cTn) assays for early rule-out of non-ST-segment elevation myocardial infarction (NSTEMI) in adults presenting with acute chest pain. METHODS: Sixteen databases were searched to September 2019. Review methods followed published guidelines. The bivariate model was used to estimate summary sensitivity and specificity with 95% confidence intervals for meta-analyses involving 4 or more studies, otherwise random-effects logistic regression was used. RESULTS: Thirty-seven studies (124 publications) were included in the review. The hs-cTn test strategies evaluated in the included studies were defined by the combination of 4 factors (assay, number of tests, timing of tests, and threshold concentration or change in concentration between tests). Clinical opinion indicated a minimum acceptable sensitivity of 97%. A single test at presentation using a threshold at or near the assay limit of detection could reliably rule-out NSTEMI for a range of hs-cTn assays. Serial testing strategies, which include an immediate rule-out step, increased the proportion ruled out without loss of sensitivity. Finally, serial testing strategies without an immediate rule-out step had excellent sensitivity and specificity, but at the expense of the option for immediate patient discharge. CONCLUSION: Test strategies that comprise an initial rule-out step, based on low hs-cTn concentrations at presentation and a minimum symptom duration, and a second step for those not ruled-out that incorporates a small absolute change in hs-cTn at 1, 2, or 3 hours, produce the highest rule-out rates with a very low risk of missed NSTEMI. PROSPERO REGISTRATION: CRD42019154716.

Implementation Barriers to Value of Information Analysis in Health Technology Decision Making: Results From a Process Evaluation.

OBJECTIVES: Value of information (VOI) analysis can support health technology assessment decision making, but it is a long way from being standard use. The objective of this study was to understand barriers to the implementation of VOI analysis and propose actions to overcome these. METHODS: We performed a process evaluation of VOI analysis use within decision making on tomosynthesis versus digital mammography for use in the Dutch breast cancer population screening. Based on steering committee meeting attendance and regular meetings with analysts, we developed a list of barriers to VOI use, which were analyzed using an established diffusion model. We proposed actions to address these barriers. Barriers and actions were discussed and validated in a workshop with stakeholders representing patients, clinicians, regulators, policy advisors, researchers, and the industry. RESULTS: Consensus was reached on groups of barriers, which included characteristics of VOI analysis itself, stakeholder's attitudes, analysts' and policy makers' skills and knowledge, system readiness, and implementation in the organization. Observed barriers did not only pertain to VOI analysis itself but also to formulating the objective of the assessment, economic modeling, and broader aspects of uncertainty assessment. Actions to overcome these barriers related to organizational changes, knowledge transfer, cultural change, and tools. CONCLUSIONS: This in-depth analysis of barriers to implementation of VOI analysis and resulting actions and tools may be useful to health technology assessment organizations that wish to implement VOI analysis in technology assessment and research prioritization. Further research should focus on application and evaluation of the proposed actions in real-world assessment processes.

Exploring the Feasibility of Comprehensive Uncertainty Assessment in Health Economic Modeling: A Case Study.

OBJECTIVES: Decision makers adopt health technologies based on health economic models that are subject to uncertainty. In an ideal world, these models parameterize all uncertainties and reflect them in the cost-effectiveness probability and risk associated with the adoption. In practice, uncertainty assessment is often incomplete, potentially leading to suboptimal reimbursement recommendations and risk management. This study examines the feasibility of comprehensive uncertainty assessment in health economic models. METHODS: A state transition model on peripheral arterial disease treatment was used as a case study. Uncertainties were identified and added to the probabilistic sensitivity analysis if possible. Parameter distributions were obtained by expert elicitation, and structural uncertainties were either parameterized or explored in scenario analyses, which were model averaged. RESULTS: A truly comprehensive uncertainty assessment, parameterizing all uncertainty, could not be achieved. Expert elicitation informed 8 effectiveness, utility, and cost parameters. Uncertainties were parameterized or explored in scenario analyses and with model averaging. Barriers included time and resource constraints, also of clinical experts, and lacking guidance regarding some aspects of expert elicitation, evidence aggregation, and handling of structural uncertainty. The team's multidisciplinary expertise and existing literature and tools were facilitators. CONCLUSIONS: While comprehensive uncertainty assessment may not be attainable, improvements in uncertainty assessment in general are no doubt desirable. This requires the development of detailed guidance and hands-on tutorials for methods of uncertainty assessment, in particular aspects of expert elicitation, evidence aggregation, and handling of structural uncertainty. The issue of benefits of uncertainty assessment versus time and resources needed remains unclear.

Cost-effectiveness of Digital Breast Tomosynthesis in Population-based Breast Cancer Screening: A Probabilistic Sensitivity Analysis.

BackgroundDigital breast tomosynthesis (DBT) is a promising screening test, but its outcomes and cost-effectiveness remain uncertain.PurposeTo determine if biennial DBT is cost-effective in a screening setting, when compared with digital mammography (DM) in the Netherlands, and to quantify the uncertainty.Materials and MethodsIn this study, performed from March 2018 to February 2019, the MIcrosimulation SCreening ANalysis model was used to conduct a probabilistic sensitivity analysis (PSA), consisting of 10 000 model runs with 1 000 000 women simulated per run. The Bayesian Cost-Effectiveness Analysis package and the Sheffield Accelerated Value of Information tool were used to process PSA outcomes. Two simulated cohorts born in 1970 were invited to undergo biennial screening between ages 50 and 74 years-one cohort was assigned to DM screening, and one was assigned to DBT screening. DM input parameters were based on data from the Dutch breast cancer screening program. DBT parameters were based on literature and expert opinion. Willingness-to-pay thresholds of €20 000 ($22 000) and €35 000 ($38 500) per life-year gained (LYG) were considered. Effects and costs were discounted at 3.5% per year.ResultsDBT resulted in a gain of 13 additional life-years per 1000 women invited to screening (7% increase, 13 of 193), followed over lifetime, compared with DM and led to 2% (four of 159) fewer false-positive results. DBT screening led to incremental discounted lifetime effects of 5.09 LYGs (95% confidence interval: -0.80, 9.70) and an increase in lifetime costs of €137 555 ($151 311) per 1000 women (95% confidence interval: €31 093 [$34 202], €263 537 [$289 891]) compared with DM, resulting in a mean incremental cost-effectiveness ratio of €27 023 ($29 725) per LYG. The probability of DBT being more cost-effective was 0.36 at €20 000 and 0.66 at €35 000 per LYG.ConclusionSwitching from digital mammography to biennial digital breast tomosynthesis is not cost-effective at a willingness-to-pay threshold of €20 000 per life-year gained, but digital breast tomosynthesis has a higher probability of being more cost-effective than digital mammography at a threshold of €35 000 per life-year gained.© RSNA, 2020Online supplemental material is available for this article.See also the editorial by Slanetz in this issue.

Auditory predictions shape the neural responses to stimulus repetition and sensory change.

Perception is a highly active process relying on the continuous formulation of predictive inferences using short-term sensory memory templates, which are recursively adjusted based on new input. According to this idea, earlier studies have shown that novel stimuli preceded by a higher number of repetitions yield greater novelty responses, indexed by larger mismatch negativity (MMN). However, it is not clear whether this MMN memory trace effect is driven by more adapted responses to prior stimulation or rather by a heightened processing of the unexpected deviant, and only few studies have so far attempted to characterize the functional neuroanatomy of these effects. Here we implemented a modified version of the auditory frequency oddball paradigm that enables modeling the responses to both repeated standard and deviant stimuli. Fifteen subjects underwent functional magnetic resonance imaging (fMRI) while their attention was diverted from auditory stimulation. We found that deviants with longer stimulus history of standard repetitions yielded a more robust and widespread activation in the bilateral auditory cortex. Standard tones repetition yielded a pattern of response entangling both suppression and enhancement effects depending on the predictability of upcoming stimuli. We also observed that regularity encoding and deviance detection mapped onto spatially segregated cortical subfields. Our data provide a better understanding of the neural representations underlying auditory repetition and deviance detection effects, and further support that perception operates through the principles of Bayesian predictive coding.

Estimating Future Health Technology Diffusion Using Expert Beliefs Calibrated to an Established Diffusion Model.

OBJECTIVES: Estimates of future health technology diffusion, or future uptake over time, are a requirement for different analyses performed within health technology assessments. Methods for obtaining such estimates include constant uptake estimates based on expert opinion or analogous technologies and on extrapolation from initial data points using parametric curves-but remain divorced from established diffusion theory and modeling. We propose an approach to obtaining diffusion estimates using experts' beliefs calibrated to an established diffusion model to address this methodologic gap. METHODS: We performed an elicitation of experts' beliefs on future diffusion of a new preterm birth screening illustrative case study technology. The elicited quantities were chosen such that they could be calibrated to yield the parameters of the Bass model of new product growth, which was chosen based on a review of the diffusion literature. RESULTS: With the elicitation of only three quantities per diffusion curve, our approach enabled us to quantify uncertainty about diffusion of the new technology in different scenarios. Pooled results showed that the attainable number of adoptions was predicted to be relatively low compared with what was thought possible. Further research evidence improved the attainable number of adoptions only slightly but resulted in greater speed of diffusion. CONCLUSIONS: The proposed approach of eliciting experts' beliefs about diffusion and informing the Bass model has the potential to fill the methodologic gap evident in value of implementation and research, as well as budget impact and some cost-effectiveness analyses.

EQ-5D-5L versus EQ-5D-3L: The Impact on Cost Effectiveness in the United Kingdom.

OBJECTIVES: To model the relationship between the three-level (3L) and the five-level (5L) EuroQol five-dimensional questionnaire and examine how differences have an impact on cost effectiveness in case studies. METHODS: We used two data sets that included the 3L and 5L versions from the same respondents. The EuroQol Group data set (n = 3551) included patients with different diseases and a healthy cohort. The National Data Bank data set included patients with rheumatoid disease (n = 5205). We estimated a system of ordinal regressions in each data set using copula models to link responses of the 3L instrument to those of the 5L instrument and its UK tariff, and vice versa. Results were applied to nine cost-effectiveness studies. RESULTS: Best-fitting models differed between the EuroQol Group and the National Data Bank data sets in terms of the explanatory variables, copulas, and coefficients. In both cases, the coefficients of the covariates and latent factors between the 3L and the 5L instruments were significantly different, indicating that moving between instruments is not simply a uniform re-alignment of the response levels for most dimensions. In the case studies, moving from the 3L to the 5L caused a decrease of up to 87% in incremental quality-adjusted life-years gained from effective technologies in almost all cases. Incremental cost-effectiveness ratios increased, often substantially. Conversely, one technology with a significant mortality gain saw increased incremental quality-adjusted life-years. CONCLUSIONS: The 5L shifts mean utility scores up the utility scale toward full health and compresses them into a smaller range, compared with the 3L. Improvements in quality of life are valued less using the 5L than using the 3L. The 3L and the 5L can produce substantially different estimates of cost effectiveness. There is no simple proportional adjustment that can be made to reconcile these differences.

Functional dissociation between regularity encoding and deviance detection along the auditory hierarchy.

Auditory deviance detection based on regularity encoding appears as one of the basic functional properties of the auditory system. It has traditionally been assessed with the mismatch negativity (MMN) long-latency component of the auditory evoked potential (AEP). Recent studies have found earlier correlates of deviance detection based on regularity encoding. They occur in humans in the first 50 ms after sound onset, at the level of the middle-latency response of the AEP, and parallel findings of stimulus-specific adaptation observed in animal studies. However, the functional relationship between these different levels of regularity encoding and deviance detection along the auditory hierarchy has not yet been clarified. Here we addressed this issue by examining deviant-related responses at different levels of the auditory hierarchy to stimulus changes varying in their degree of deviation regarding the spatial location of a repeated standard stimulus. Auditory stimuli were presented randomly from five loudspeakers at azimuthal angles of 0°, 12°, 24°, 36° and 48° during oddball and reversed-oddball conditions. Middle-latency responses and MMN were measured. Our results revealed that middle-latency responses were sensitive to deviance but not the degree of deviation, whereas the MMN amplitude increased as a function of deviance magnitude. These findings indicated that acoustic regularity can be encoded at the level of the middle-latency response but that it takes a higher step in the auditory hierarchy for deviance magnitude to be encoded, thus providing a functional dissociation between regularity encoding and deviance detection along the auditory hierarchy.

When Future Change Matters: Modeling Future Price and Diffusion in Health Technology Assessments of Medical Devices.

BACKGROUND: Health technology assessments (HTAs) that take account of future price changes have been examined in the literature, but the important issue of price reductions that are generated by the reimbursement decision has been ignored. OBJECTIVES: To explore the impact of future price reductions caused by increasing uptake on HTAs and decision making for medical devices. METHODS: We demonstrate the use of a two-stage modeling approach to derive estimates of technology price as a consequence of changes in technology uptake over future periods on the basis of existing theory and supported by empirical studies. We explore the impact on cost-effectiveness and expected value of information analysis in an illustrative example on the basis of a technology in development for preterm birth screening. RESULTS: The application of our approach to the case study technology generates smaller incremental cost-effectiveness ratios compared with the commonly used single cohort approach. The extent of this reduction in the incremental cost-effectiveness ratio depends on the magnitude of the modeled price reduction, the speed of diffusion, and the length of the assumed technology life horizon. Results of value of information analysis are affected through changes in the expected net benefit calculation, the addition of uncertain parameters, and the diffusion-adjusted estimate of the affected patient population. CONCLUSIONS: Because modeling future changes in price and uptake has the potential to affect HTA outcomes, modeling techniques that can address such changes should be considered for medical devices that may otherwise be rejected.

Repetition suppression and repetition enhancement underlie auditory memory-trace formation in the human brain: an MEG study.

The formation of echoic memory traces has traditionally been inferred from the enhanced responses to its deviations. The mismatch negativity (MMN), an auditory event-related potential (ERP) elicited between 100 and 250ms after sound deviation is an indirect index of regularity encoding that reflects a memory-based comparison process. Recently, repetition positivity (RP) has been described as a candidate ERP correlate of direct memory trace formation. RP consists of repetition suppression and enhancement effects occurring in different auditory components between 50 and 250ms after sound onset. However, the neuronal generators engaged in the encoding of repeated stimulus features have received little interest. This study intends to investigate the neuronal sources underlying the formation and strengthening of new memory traces by employing a roving-standard paradigm, where trains of different frequencies and different lengths are presented randomly. Source generators of repetition enhanced (RE) and suppressed (RS) activity were modeled using magnetoencephalography (MEG) in healthy subjects. Our results show that, in line with RP findings, N1m (~95-150ms) activity is suppressed with stimulus repetition. In addition, we observed the emergence of a sustained field (~230-270ms) that showed RE. Source analysis revealed neuronal generators of RS and RE located in both auditory and non-auditory areas, like the medial parietal cortex and frontal areas. The different timing and location of neural generators involved in RS and RE points to the existence of functionally separated mechanisms devoted to acoustic memory-trace formation in different auditory processing stages of the human brain.

Two sequential processes of change detection in hierarchically ordered areas of the human auditory cortex.

Auditory deviance detection occurs around 150 ms after the onset of a deviant sound. Recent studies in animals and humans have described change-related processes occurring during the first 50 ms after sound onset. However, it still remains an open question whether these early and late processes of deviance detection are organized hierarchically in the human auditory cortex. We applied a beamforming source reconstruction approach in order to estimate brain sources associated with 2 temporally distinct markers of deviance detection. Results showed that rare frequency changes elicit an enhancement of the Nbm component of the middle latency response (MLR) peaking at 43 ms, in addition to the magnetic mismatch negativity (MMNm) peaking at 115 ms. Sources of MMNm, located in the right superior temporal gyrus, were lateral and posterior to the deviance-related MLR activity being generated in the right primary auditory cortex. Source reconstruction analyses revealed that detection of changes in the acoustic environment is a process accomplished in 2 different time ranges, by spatially separated auditory regions. Paralleling animal studies, our findings suggest that primary and secondary areas are involved in successive stages of deviance detection and support the existence of a hierarchical network devoted to auditory change detection.

Encoding of nested levels of acoustic regularity in hierarchically organized areas of the human auditory cortex.

Our auditory system is able to encode acoustic regularity of growing levels of complexity to model and predict incoming events. Recent evidence suggests that early indices of deviance detection in the time range of the middle-latency responses (MLR) precede the mismatch negativity (MMN), a well-established error response associated with deviance detection. While studies suggest that only the MMN, but not early deviance-related MLR, underlie complex regularity levels, it is not clear whether these two mechanisms interplay during scene analysis by encoding nested levels of acoustic regularity, and whether neuronal sources underlying local and global deviations are hierarchically organized. We registered magnetoencephalographic evoked fields to rapidly presented four-tone local sequences containing a frequency change. Temporally integrated local events, in turn, defined global regularities, which were infrequently violated by a tone repetition. A global magnetic mismatch negativity (MMNm) was obtained at 140-220 ms when breaking the global regularity, but no deviance-related effects were shown in early latencies. Conversely, Nbm (45-55 ms) and Pbm (60-75 ms) deflections of the MLR, and an earlier MMNm response at 120-160 ms, responded to local violations. Distinct neuronal generators in the auditory cortex underlay the processing of local and global regularity violations, suggesting that nested levels of complexity of auditory object representations are represented in separated cortical areas. Our results suggest that the different processing stages and anatomical areas involved in the encoding of auditory representations, and the subsequent detection of its violations, are hierarchically organized in the human auditory cortex.