Quantitative Model-based Analyses Research Articles

Procedural auditory category learning is selectively disrupted in developmental language disorder.

Speech communication depends on accurate perception and identification of speech sounds, which vary across talkers and word or sentence contexts. The ability to map this variable input onto discrete speech sound representations relies on categorization. Recent research and theoretical models implicate the procedural learning system in the ability to learn novel speech and non-speech categories. This connection is particularly intriguing because several language disorders that demonstrate linguistic impairments are proposed to stem from procedural learning and memory dysfunction. One such disorder, Developmental Language Disorder (DLD), affects 7.5% of children and persists into adulthood. While DLD is associated with general linguistic impairments, it is not yet clear how fundamental perceptual and cognitive processes supporting language are impacted, such as the ability to learn novel auditory categories. We examined auditory category learning in children with DLD and typically developed (TD) children using two well-matched nonspeech auditory category learning challenges to draw upon presumed procedural (information-integration) versus declarative (rule-based) learning systems. We observed impaired information-integration category learning and intact rule-based category learning in the DLD group. Quantitative model-based analyses revealed reduced use of, and slower shifting to, optimal procedural-based strategies in DLD and slower shifting to but similarly efficient use of optimal hypothesis-testing strategies. The dissociation is consistent with the Procedural Deficit Hypothesis of language disorders and supports the theoretical distinction of multiple category learning systems. These findings demonstrate that highly controlled experimental tasks assessing perceptual and cognitive abilities can relate to real-world challenges facing individuals with DLD in forming stable linguistic representations.

Abstract CT272: Pharmacodynamic and immunophenotyping analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301)

Abstract Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, a potent, selective, orally administered ATR inhibitor with antitumor activity in preclinical models, was evaluated in Part A1 of an open-label, single-arm study (NCT04170153) for safety, tolerability, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). M1774 monotherapy in patients with advanced solid tumors was well-tolerated and the totality of evidence, including quantitative model-based analyses, suggested the recommended dose for expansion (RDE) as 180 mg QD 2 weeks on/1 week off.1 Here, we report findings of the M1774 PD and immunophenotyping analyses. Methods: M1774 PD was explored by assessing phosphorylation by ATR of CHK1 (p-CHK1) in tumor and of H2AX (γ-H2AX) in serial blood samples, stimulated ex vivo with the radiomimetic 4-Nitroquinoline N-oxide or Dimethyl sulfoxide as control. A flow cytometry quantitative assay was used to measure γ-H2AX in the CD45+ lymphocytes fraction. The effect of M1774 on the immunophenotype was explored by flow cytometry. Blood samples were collected at baseline, 3 and 24 hours after first M1774 administration on day 1 of cycle 1 for the γ-H2AX analysis, and on Days 1 and 15 of Cycles 1 and 2 before treatment for immunophenotyping. Results: Preclinical tumor tissue-blood bridging PD analyses in a mouse model demonstrated that the inhibition of γ-H2AX in lymphocytes highly correlated with inhibition of p-CHK1 in tumor. Clinical data of γ-H2AX levels and immunophenotyping were generated for the blood samples collected from the 55 participants of Part A1 of the study. Exploratory PK-PD analysis using γ-H2AX levels 3 h post-dose on day 1 across the doses predicted target inhibition >80% for doses ≥130 mg, suggesting target engagement. The levels of ɣ-H2AX at 24 h after first dose intake were variable and mean levels rebounded to baseline value. M1774 treatment did not cause any significant and consistent change in the levels of all explored immune cell subsets at the tested dose levels, including myeloid-derived suppressor cells, T and B lymphocytes, monocytes, and natural killer cells. Conclusions: PD analyses showed that M1774 efficiently inhibited ATR at the RDE without impacting the immunophenotype. 1TA Yap, et al. Ann Oncol. 2022; 33(suppl_7): S197-S224. Citation Format: Ruth Plummer, Anthony W. Tolcher, Timothy A. Yap, Giuseppe Sessa, Jatinder K. Mukker, Annick Seithel-Keuth, Christine Hicking, Zoltan Szucs, Ioannis Gounaris, Giuseppe Locatelli, Johann S. de Bono. Pharmacodynamic and immunophenotyping analyses of ATR inhibitor M1774 in a Phase I study in patients with solid tumors (DDRiver Solid Tumors 301) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT272.

Impaired and Spared Auditory Category Learning in Developmental Dyslexia

Categorization has a deep impact on behavior, but whether category learning is served by a single system or multiple systems remains debated. Here, we designed two well-equated nonspeech auditory category learning challenges to draw on putative procedural (information-integration) versus declarative (rule-based) learning systems among adult Hebrew-speaking control participants and individuals with dyslexia, a language disorder that has been linked to a selective disruption in the procedural memory system and in which phonological deficits are ubiquitous. We observed impaired information-integration category learning and spared rule-based category learning in the dyslexia group compared with the neurotypical group. Quantitative model-based analyses revealed reduced use of, and slower shifting to, optimal procedural-based strategies in dyslexia with hypothesis-testing strategy use on par with control participants. The dissociation is consistent with multiple category learning systems and points to the possibility that procedural learning inefficiencies across categories defined by complex, multidimensional exemplars may result in difficulty in phonetic category acquisition in dyslexia.

Flexible Coding of Visual Working Memory Representations during Distraction.

Visual working memory (VWM) recruits a broad network of brain regions, including prefrontal, parietal, and visual cortices. Recent evidence supports a "sensory recruitment" model of VWM, whereby precise visual details are maintained in the same stimulus-selective regions responsible for perception. A key question in evaluating the sensory recruitment model is how VWM representations persist through distracting visual input, given that the early visual areas that putatively represent VWM content are susceptible to interference from visual stimulation.To address this question, we used a functional magnetic resonance imaging inverted encoding model approach to quantitatively assess the effect of distractors on VWM representations in early visual cortex and the intraparietal sulcus (IPS), another region previously implicated in the storage of VWM information. This approach allowed us to reconstruct VWM representations for orientation, both before and after visual interference, and to examine whether oriented distractors systematically biased these representations. In our human participants (both male and female), we found that orientation information was maintained simultaneously in early visual areas and IPS in anticipation of possible distraction, and these representations persisted in the absence of distraction. Importantly, early visual representations were susceptible to interference; VWM orientations reconstructed from visual cortex were significantly biased toward distractors, corresponding to a small attractive bias in behavior. In contrast, IPS representations did not show such a bias. These results provide quantitative insight into the effect of interference on VWM representations, and they suggest a dynamic tradeoff between visual and parietal regions that allows flexible adaptation to task demands in service of VWM.SIGNIFICANCE STATEMENT Despite considerable evidence that stimulus-selective visual regions maintain precise visual information in working memory, it remains unclear how these representations persist through subsequent input. Here, we used quantitative model-based fMRI analyses to reconstruct the contents of working memory and examine the effects of distracting input. Although representations in the early visual areas were systematically biased by distractors, those in the intraparietal sulcus appeared distractor-resistant. In contrast, early visual representations were most reliable in the absence of distraction. These results demonstrate the dynamic, adaptive nature of visual working memory processes, and provide quantitative insight into the ways in which representations can be affected by interference. Further, they suggest that current models of working memory should be revised to incorporate this flexibility.

Integrated Simulation Framework for Toxicity, Dose Intensity, Disease Progression, and Cost Effectiveness for Castration-Resistant Prostate Cancer Treatment With Eribulin.

Quantitative model-based analyses are helpful to support decision-making in drug development. In oncology, disease progression/clinical outcome (DPCO) models have been used for early predictions of clinical outcome, but most of such approaches did not include adverse events or dose intensity. In addition, cost-effectiveness evaluations of investigational compounds are becoming increasingly important. Here, we developed an integrated model-based framework including relevant treatment effects for patients with castration-resistant prostate cancer treated with the anticancer agent eribulin. The framework included (i) a DPCO model relating prostate-specific antigen (PSA) dynamics to survival; (ii) models for adverse events including dose-limiting neutropenia and other graded toxicities; (iii) a model for Eastern Cooperative Oncology Group (ECOG) performance score; (iv) a model for dropout; (v) the consideration of cost effectiveness. The model allowed simulation of realistic treatment courses. Subsequently, simulations evaluating alternative treatment protocols or patient characteristics were performed in order to derive inferences on expected efficacy and cost effectiveness.

Evaluating the use of a continuous approximation for model-based quantification of pulsed chemical exchange saturation transfer (CEST)

Many potential clinical applications of chemical exchange saturation transfer (CEST) have been studied in recent years. However, due to various limitations such as specific absorption rate guidelines and scanner hardware constraints, most of the proposed applications have yet to be translated into routine diagnostic tools. Currently, pulsed CEST which uses multiple short pulses to perform the saturation is the only viable irradiation scheme for clinical translation. However, performing quantitative model-based analysis on pulsed CEST is time consuming because it is necessary to account for the time dependent amplitude of the saturation pulses. As a result, pulsed CEST is generally treated as continuous CEST by finding its equivalent average field or power. Nevertheless, theoretical analysis and simulations reveal that the resulting magnetization is different when the different irradiation schemes are applied. In this study, the quantification of important model parameters such as the amine proton exchange rate from a pulsed CEST experiment using quantitative model-based analyses were examined. Two model-based approaches were considered – discretized and continuous approximation to the time dependent RF irradiation pulses. The results showed that the discretized method was able to fit the experimental data substantially better than its continuous counterpart, but the smaller fitted error of the former did not translate to significantly better fit for the important model parameters. For quantification of the endogenous CEST effect, such as in amide proton transfer imaging, a model-based approach using the average power equivalent saturation can thus be used in place of the discretized approximation.

Stimulus modality interacts with category structure in perceptual category learning

Two experiments were conducted that examined information integration and rule-based category learning, using stimuli that contained auditory and visual information. The results suggest that it is easier to perceptually integrate information within these sensory modalities than across modalities. Conversely, it is easier to perform a disjunctive rule-based task when information comes from different sensory modalities, rather than from the same modality. Quantitative model-based analyses suggested that the information integration deficit for across-modality stimulus dimensions was due to an increase in the use of hypothesis-testing strategies to solve the task and to an increase in random responding. The modeling also suggested that the across-modality advantage for disjunctive, rule-based category learning was due to a greater reliance on disjunctive hypothesis-testing strategies, as opposed to unidimensional hypothesis-testing strategies and random responding.

Striatal contributions to category learning: quantitative modeling of simple linear and complex nonlinear rule learning in patients with Parkinson's disease.

The contribution of the striatum to category learning was examined by having patients with Parkinson's disease (PD) and matched controls solve categorization problems in which the optimal rule was linear or nonlinear using the perceptual categorization task. Traditional accuracy-based analyses, as well as quantitative model-based analyses were performed. Unlike accuracy-based analyses, the model-based analyses allow one to quantify and separate the effects of categorization rule learning from variability in the trial-by-trial application of the participant's rule. When the categorization rule was linear, PD patients showed no accuracy, categorization rule learning, or rule application variability deficits. Categorization accuracy for the PD patients was associated with their performance on a test believed to be sensitive to frontal lobe functioning. In contrast, when the categorization rule was nonlinear, the PD patients showed accuracy, categorization rule learning, and rule application variability deficits. Furthermore, categorization accuracy was not associated with performance on the test of frontal lobe functioning. Implications for neuropsychological theories of categorization learning are discussed.

A possible role of the striatum in linear and nonlinear category learning: evidence from patients with Huntington's disease.

Linear and nonlinear categorization rule learning was examined in patients with Huntington's disease (HD) and a group of controls using the perceptual categorization task. Participants learned to categorize simple line stimuli into 1 of 2 categories over 600 trials. In addition to traditional measures of accuracy, quantitative model-based analyses were applied to each participant's data to characterize better the nature of any observed deficits. In the linear rule condition, HD patients displayed an early-training deficit relative to controls, whereas later in training the HD patients were not statistically different from controls. In the nonlinear rule condition, HD patients displayed both an early- and late-training deficit. The quantitative model-based analyses revealed that the HD patients' deficits in the linear condition were due to an impairment in learning the experimenter-defined rule and not in applying a learned rule inconsistently. In the nonlinear condition, in contrast, the HD patients' deficits were due to an impairment in learning the experimenter-defined rule and in applying a learned rule inconsistently. Overall, these results suggest that HD can result in a deficit in learning both linear and nonlinear categorization rules.