Regioselective Syntheses of 2,3,5-Trisubstituted Pyridines via 5-Chloro-3-fluoro-2-(methylsulfonyl)pyridine.

We report the high-yielding, large-scale, one-pot synthesis of two versatile building blocks (1-Cl and 1-Br) for the regioselective synthesis of a variety of 2,3,5-trisubstituted pyridines from inexpensive materials. These molecules are readily derivatized at positions 2, 3, and 5. These building blocks can also be used for the synthesis of fused pyrido-oxazines and for the synthesis of 2,3,4,5-tetrasubstituted pyridines.

The English Sublexical Toolkit: Methods for indexing sound-spelling consistency.

This work introduces the English Sublexical Toolkit, a suite of tools that utilizes an experience-dependent learning framework of sublexical knowledge to extract regularities from the English lexicon. The Toolkit quantifies the empirical regularity of sublexical units in both the reading and spelling directions (i.e., grapheme-to-phoneme and phoneme-to-grapheme) and at multiple grain sizes (i.e., phoneme/grapheme and onset/rime unit size). It can extract multiple experience-dependent regularity indices for words or pseudowords, including both frequency indices (e.g., grapheme frequency) and conditional probability indices (e.g., grapheme-to-phoneme probability). These tools provide (1) superior estimates of the regularities that better reflect the complexity of the sublexical system relative to previously published indices and (2) completely novel indices of sublexical units such as phonographeme frequency (i.e., combined units of individual phonemes and graphemes that are independent of processing direction). We demonstrate that measures from the toolkit explain significant amounts of variance in empirical data (naming of real words and lexical decision), and either outperform or are comparable to the best available consistency measures. The flexibility of the toolkit is further demonstrated by its ability to readily index the probability of different pseudowords pronunciations, and we report that the measures account for the majority of variance in these empirically observed probabilities. Overall, this work provides a framework and resources that can be flexibly used to identify optimal corpus-based consistency measures that help explain reading/spelling behaviors for real and pseudowords.

Cortical and Subcortical Mechanisms of Orthographic Word-form Learning.

We examined the initial stages of orthographic learning in real time as literate adults learned spellings for spoken pseudowords during fMRI scanning. Participants were required to learn and store orthographic word forms because the pseudoword spellings were not uniquely predictable from sound to letter mappings. With eight learning trials per word form, we observed changes in the brain's response as learning was taking place. Accuracy was evaluated during learning, immediately after scanning, and 1 week later. We found evidence of two distinct learning systems-hippocampal and neocortical-operating during orthographic learning, consistent with the predictions of dual systems theories of learning/memory such as the complementary learning systems framework [McClelland, J. L., McNaughton, B. L., & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419-457, 1995]. The bilateral hippocampus and the visual word form area (VWFA) showed significant BOLD response changes over learning, with the former exhibiting a rising pattern and the latter exhibiting a falling pattern. Moreover, greater BOLD signal increase in the hippocampus was associated with better postscan recall. In addition, we identified two distinct bilateral brain networks that mirrored the rising and falling patterns of the hippocampus and VWFA. Functional connectivity analysis revealed that regions within each network were internally synchronized. These novel findings highlight, for the first time, the relevance of multiple learning systems in orthographic learning and provide a paradigm that can be used to address critical gaps in our understanding of the neural bases of orthographic learning in general and orthographic word-form learning specifically.

Increased neural differentiation after a single session of aerobic exercise in older adults.

Aging is associated with decreased cognitive function. One theory posits that this decline is in part due to multiple neural systems becoming dedifferentiated in older adults. Exercise is known to improve cognition in older adults, even after only a single session. We hypothesized that one mechanism of improvement is a redifferentiation of neural systems. We used a within-participant, cross-over design involving 2 sessions: either 30 minutes of aerobic exercise or 30 minutes of seated rest (n = 32; ages 55-81 years). Both functional Magnetic Resonance Imaging (fMRI) and Stroop performance were acquired soon after exercise and rest. We quantified neural differentiation via general heterogeneity regression. There were 3 prominent findings following the exercise. First, participants were better at reducing Stroop interference. Second, while there was greater neural differentiation within the hippocampal formation and cerebellum, there was lower neural differentiation within frontal cortices. Third, this greater neural differentiation in the cerebellum and temporal lobe was more pronounced in the older ages. These data suggest that exercise can induce greater neural differentiation in healthy aging.

Interpolated retrieval retroactively increases recall and promotes cross-episode memory interdependence.

Retrieving existing memories before new learning can lead to retroactive facilitation. Three experiments examined whether interpolated retrieval is associated with retroactive facilitation and memory interdependence that reflects integrative encoding. Participants studied two lists of cue-response word pairs that repeated across lists (A-B, A-B), appeared in list 1 (A-B, -), or included the same cues with changed responses in each list (A-B, A-C). For A-B, A-C pairs, the tasks interpolated between lists required recall of list 1 (B) responses (with or without feedback) or restudy of complete list 1 (A-B) pairs. In list 2, participants only studied pairs (experiment 1) or studied pairs, attempted to detect changed (C) responses, and attempted to recall list 1 responses for detected changes (experiments 2 and 3). On a final cued recall test, participants attempted to recall list 1 responses, indicated whether responses changed between lists, and if so, attempted to recall list 2 responses. Interpolated retrieval was associated with subsequent retroactive facilitation and greater memory interdependence for B and C responses. These correlational findings are compatible with the view that retrieval retroactively facilitates memories, promotes coactivation of existing memories and new learning, and enables integrative encoding that veridically binds information across episodes.

The right hemisphere's capacity for language: evidence from primary progressive aphasia.

The role of the right hemisphere (RH) in core language processes is still a matter of intense debate. Most of the relevant evidence has come from studies of gray matter, with relatively little research on RH white matter (WM) connectivity. Using Diffusion Tensor Imaging-based tractography, the current work examined the role of the two hemispheres in language processing in 33 individuals with Primary Progressive Aphasia (PPA), aiming to better characterize the contribution of the RH to language processing in the context of left hemisphere (LH) damage. The findings confirm the impact of PPA on the integrity of the WM language tracts in the LH. Additionally, an examination of the relationship between tract integrity and language behaviors provides robust evidence of the involvement of the WM language tracts of both hemispheres in language processing in PPA. Importantly, this study provides novel evidence of a unique contribution of the RH to language processing (i.e. a contribution independent from that of the language-dominant LH). Finally, we provide evidence that the RH contribution is specific to language processing rather than being domain general. These findings allow us to better characterize the role of RH in language processing, particularly in the context of LH damage.

Written discourse in diagnosis for acquired neurogenic communication disorders: current evidence and future directions.

Purpose: We aimed to perform the first review of research focusing on written discourse performance in people with acquired neurogenic communication disorders. In studies from 2000 onward, we specifically sought to determine: (1) the differences between patient populations and control groups, (2) the differences between different patient populations, (3) longitudinal differences between patient populations, and (4) modality differences between spoken and written discourse performance. Methods: We completed a thorough search on MEDLINE, Embase, Cochrane, APAPsycinfo, Web of Science, and Scopus databases. We identified studies that focus on written discourse performance in people with aphasia, primary progressive aphasia, mild cognitive impairment, and Alzheimer's disease. Results: Nineteen studies were identified from the review of literature, some of which addressed more than one of our review questions. Fifteen studies included a comparison between clinical populations and controls. Six studies compared different characteristics of patient populations. Three studies reported changes over time in progressive disorders. Six studies targeted different modalities of discourse. Conclusion: Differences in linguistic features by patient populations are not yet clear due to the limited number of studies and different measures and tasks used across the studies. Nevertheless, there is substantial evidence of numerous linguistic features in acquired neurogenic communication disorders that depart from those of healthy controls. Compared to the controls, people with aphasia tend to produce fewer words, and syntactically simpler utterances compared to the controls. People with Alzheimer's disease produce less information content, and this feature increases over time, as reported in longitudinal studies. Our review imparts additional information that written and spoken discourse provide unique insights into the cognitive and linguistic deficits experienced by people with aphasia, Alzheimer's disease, mild cognitive impairment and primary progressive aphasia and provide targets for treatment to improve written communication in these groups.

Pseudoword spelling: insights into sublexical representations and lexical interactions.

ABSTRACTIn this work we introduce a new tool for measuring English spelling-sound consistency, the PG Toolkit, which we use to conduct detailed analyses of pseudoword spellings that provide new insights into the nature of sublexical and lexical representations. There are several key findings: first, sound-spelling consistency measured at two different "grain sizes", phonographeme and onset/rime, each explained unique variance in pseudoword spelling. Second, lexical skill was more related to pseudoword accuracy at the onset/rime level than at the phonographeme level, and individuals who chose more consistent mappings to spell pseudowords tended to have better lexical skill. Finally, no unique contribution of consistency in the reading direction ("feedback") was found after controlling for consistency in the spelling direction. Taken together, the results validate the various measures provided by the PG Toolkit and establish new evidence that supports an interpretation of sublexical processes as operations over hierarchically-structured representations.

Dearomatization of Cyclic Diphenylhydrazines: Harnessing the o-Semidine Rearrangement for the Synthesis of Spirocyclic Tetrahydroquinolines.

The synthesis of novel tetrahydroquinoline-containing spirocycles has been achieved through an acid-promoted dearomatization of cyclic diarylhydrazines. The reaction, proceeding through a dearomative o-semidine rearrangement, furnishes a stable, yet reactive spirocyclohexadieniminium ion, which can further be used as an electrophile or a diene in a one-pot sequence. These transformations efficiently produce novel diazaspirocycles and allow for further synthetic elaboration of the cyclohexadienamine products.

Treatment of the Linguistic and Temporal Components of Lexical Activation to Improve Word Retrieval in Aphasia.

Current approaches to treatments for word processing impairments in aphasia emphasize two components to target, the linguistic content, semantic or phonological representations of words, and the processing component, access to and retrieval of those representations. In this study, we explore these two components of a treatment to improve lexical activation that supports access and retrieval of word representations. Five people with aphasia participated. The treatment task was repetition of concrete word pairs after a 5-s response delay which was intended to provide practice in maintaining activation of the words for that 5-s period before reproducing them. Two of the five participants demonstrated a difficulty in maintaining activation of single words in repetition, with accuracy decreasing significantly after the 5-s interval. The treatment was applied to all participants, however, to determine if its benefit was specific to those with the activation maintenance impairment. Results confirmed that the activation maintenance treatment in the context of this repetition task led to more treatment gains for the two participants who demonstrated this specific impairment. They made gains on four of the nine measures compared to improvements on one to two measures for the other participants. A second question addressed in this study was the relative importance of the item component (linguistic content) of the treatment and the processing component, maintenance of activation. To that end, there were two conditions of treatment probes, (1) repeated content for all treatment, immediate post-treatment and 3-month maintenance probes and (2) novel content for probes in these three phases of treatment. Only one participant showed significant improvement in treatment when items were novel for all probes. We discuss the possibility that this outcome reflects a more specific deficit in the temporal processing component of lexical activation compared to the two other participants who showed better performance on probes with repeated items in treatment and post-treatment phases. Clinical implications of this study and directions of future research are discussed.

Pseudoword spelling ability predicts response to word spelling treatment in acquired dysgraphia.

Although rehabilitation of acquired dysgraphia can be quite effective, identifying predictors of responsiveness to treatment is useful for prognosis and individualization of treatment protocols. This study examined whether various features of treatment response were predicted by the integrity of one or more of the central cognitive components of spelling: orthographic long-term memory, orthographic working memory, and phoneme-grapheme conversion. Twenty dysgraphic individuals received 12 weeks of bi-weekly, individualized, lexically-based spelling rehabilitation using a spell-study-spell paradigm. Linear multiple regression modelling examined whether the type and severity of the dysgraphic deficit, assessed before rehabilitation, predicted the magnitude and rate of improvement, generalization to untrained items and maintenance of treatment gains. The results revealed that pseudoword spelling accuracy - indexing the integrity of the phoneme-grapheme conversion system - was the only factor examined that significantly predicted the rate of accuracy gains for trained words as well as the extent of generalization to untrained words. Pre-treatment pseudoword spelling accuracy also predicted retention of gains for trained and untrained words at 3-month follow-up. These findings reveal that the integrity of the phoneme-grapheme conversion system prior to dysgraphia rehabilitation may play a key role in rehabilitation-driven recovery, even when the treatment approach targets lexical rather than pseudoword spelling processes.

Decoding complex emotions and humanization show related face processing effects.

Inferring others' complex emotions is central to ascribing humanness to others. However, little past research has investigated the perceptual processes linking the inference of complex emotions to judging others' humanness. To this end, we disrupted the low-level perceptual processes typically employed in face processing via face inversion. Of interest was whether the inversion-driven deficits in complex emotion judgments and in humanness judgments were related. In three experiments, we find that disrupting efficient face processing via face inversion undermined the accurate decoding of complex emotions from the eyes (Experiments 1a, 1b, and 2) and triggered more dehumanized evaluations of target eye regions (Experiments 1a and 1b) and faces (Experiment 2). Critically, these inversion effects on emotion decoding and dehumanization were positively correlated. People who demonstrated stronger inversion effects on the accuracy of decoding complex emotions also demonstrated stronger inversion effects on dehumanizing evaluations. Taken together, these findings provide novel evidence that sensitivity to complex emotions and (de)humanization are related through a shared perceptual basis in efficient face processing. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Spatial frequency and valence interact in complex emotion perception.

Research on spatial frequency contributions to facial emotion identification has largely focused on basic emotions. The present experiment characterised spatial frequency contributions to decoding complex emotions, which can be less visible and intense than basic emotions. We investigated the effects of spatial frequency, expression valence and perceptually available features (full face or eyes only) on decoding accuracy. We observed main effects of all factors, with better performance for high (relative to low) spatial frequency, for positive (relative to negative) emotions and for full face (relative to eyes only) conditions. We also observed an interaction of all factors. The high spatial frequency advantage in decoding accuracy was eliminated only for full faces expressing more positive complex emotions. These findings suggest advantages from high spatial frequency content in accurately decoding complex emotions may attenuate when positive complex emotions are decoded from the spatial frequency content of a broader constellation of features.

The Effects of Handwriting Experience on Literacy Learning.

Previous research indicates that writing practice may be more beneficial than nonmotor practice for letter learning. Here, we report a training study comparing typing, visual, and writing learning conditions in adults (N = 42). We investigated the behavioral consequences of learning modality on literacy learning and evaluated the nature of the learned letter representations. Specifically, the study addressed three questions. First, are the benefits of handwriting practice due to motor learning per se or to other incidental factors? Second, do the benefits generalize to untrained tasks? And third, does handwriting practice lead to learning and strengthening only of motor representations or of other types of representations as well? Our results clearly show that handwriting compared with nonmotor practice produces faster learning and greater generalization to untrained tasks than previously reported. Furthermore, only handwriting practice leads to learning of both motor and amodal symbolic letter representations.

Synthesis and Spectrophotometric Analysis of 1-Azafluorenone Derivatives.

A new extension for the 'one pot' construction of diverse 1-azafluorene derivatives featuring a Diels-Alder/retro-Diels-Alder cycloaddition is reported. Conditions were also determined for oxidation to the derived azafluorenones. The spectrophotometric analysis of five different azafluorenones were performed. Moderate fluorescence was observed with azafluorenone derivatives that bear an imbedded pyridone motif; whereas those bearing substituted pyridines do not fluoresce.

Re-learning to be different: Increased neural differentiation supports post-stroke language recovery.

Identifying the neural changes that support recovery of cognitive functions after a brain lesion is important to advance our understanding of human neuroplasticity, which, in turn, forms the basis for the development of effective treatments. To date, the preponderance of neuroimaging studies has focused on localizing changes in average brain activity associated with functional recovery. Here, we took a novel approach by evaluating whether cognitive recovery in chronic stroke is related to increases in the differentiation of local neural response patterns. This approach is supported by research indicating that, in the intact brain, local neural representations become more differentiated (dissimilar) with learning (Glezer et al., 2015). We acquired fMRI data before and after 21 individuals received approximately 12 weeks of behavioral treatment for written language impairment due to a left-hemisphere stroke. We used Local-Heterogeneity Regression Analysis (Purcell and Rapp, 2018) to measure local neural response differentiation associated with written language processing, assuming that greater heterogeneity in the pattern of activity across adjacent neural areas indicates more well-differentiated neural representations. First, we observed pre to post-treatment increases in local neural differentiation (Local-Hreg) in the ventral occipital-temporal cortex of the left hemisphere. Second, we found that, in this region, higher local neural response differentiation prior to treatment was associated with less severe written language impairment, and that it also predicted greater future responsiveness to treatment. Third, we observed that changes in neural differentiation were systematically related to performance changes for trained and untrained items. Fourth, we did not observe these brain-behavior relationships for mean BOLD responses, only for Local-Hreg. Thus, this is the first investigation to quantify changes in local neural differentiation in the recovery of a cognitive function and the first to demonstrate the clear behavioral relevance of these changes. We conclude that the findings provide strong support for the novel hypothesis that the local re-differentiation of neural representations can play a significant role in functional recovery after brain lesion.

The use of spelling for variant classification in primary progressive aphasia: Theoretical and practical implications.

Currently, variant subtyping in primary progressive aphasia (PPA) requires an expert neurologist and extensive language and cognitive testing. Spelling impairments appear early in the development of the disorder, and the three PPA variants (non-fluent - nfvPPA; semantic - svPPA; logopenic - lvPPA) reportedly show fairly distinct spelling profiles. Given the theoretical and empirical evidence indicating that spelling may serve as a proxy for spoken language, the current study aimed to determine whether spelling performance alone, when evaluated with advanced statistical analyses, allows for accurate PPA variant classification. A spelling to dictation task (with real words and pseudowords) was administered to 33 PPA individuals: 17 lvPPA, 10 nfvPPA, 6 svPPA. Using machine learning classification algorithms, we obtained pairwise variant classification accuracies that ranged between 67 and 100%. In additional analyses that assumed no prior knowledge of each case's variant, classification accuracies ranged between 59 and 70%. To our knowledge, this is the first time that all the PPA variants, including the most challenging logopenic variant, have been classified with such high accuracy when using information from a single language task. These results underscore the rich structure of the spelling process and support the use of a spelling task in PPA variant classification.

Re-learning and remembering in the lesioned brain.

It is well known that re-learning language skills after a brain lesion can be very difficult. However, while learning and memory challenges have been extensively researched in amnesic individuals, very little research attention has been directed at understanding the characteristics of learning and memory that are relevant to recovery and rehabilitation of acquired language impairments. Even in the absence of damage to the medial temporal lobe regions classically associated with learning and memory, these individuals often suffer damage to frontal and other subcortical areas associated with learning and memory that may contribute to the learning challenges they face. Therefore, an understanding of the learning and memory profiles of post-stroke language impairments is important for the development and optimization of rehabilitation approaches. In two studies, we examine the degree to which certain basic characteristics of learning and memory, identified in neurotypical individuals, are intact in individuals with post-stroke language impairment. We specifically consider fundamental principles regarding the optimal spacing of learning trials that have been shown to reliably operate in neurotypical adults, across a wide range of language domains. We report on two studies that examine whether or not these principles also apply in language re-learning and retention for individuals with acquired deficits in written language production. Study 1 compared distributed vs. clustered training schedules, while Study 2 examined-for the first time in the context of re-learning-the relationship between the spacing of training trials and the retention period. This investigation revealed that, despite significant cognitive deficits and brain lesions, remarkably similar principles govern re-learning and retention in the lesioned brain as have been found to apply in neurologically healthy individuals. These results allow us to begin to integrate our understanding of recovery with the broader literature on learning and memory and have implications for the optimal organization of rehabilitation. Specifically, the findings raise questions regarding the traditional compression of rehabilitation within relatively short time windows.

Statistical analysis in Small-N Designs: using linear mixed-effects modeling for evaluating intervention effectiveness.

BACKGROUND: Advances in statistical methods and computing power have led to a renewed interest in addressing the statistical analysis challenges posed by Small-N Designs (SND). Linear mixed-effects modeling (LMEM) is a multiple regression technique that is flexible and suitable for SND and can provide standardized effect sizes and measures of statistical significance. AIMS: Our primary goals are to: 1) explain LMEM at the conceptual level, situating it in the context of treatment studies, and 2) provide practical guidance for implementing LMEM in repeated measures SND. METHODS & PROCEDURES: We illustrate an LMEM analysis, presenting data from a longitudinal training study of five individuals with acquired dysgraphia, analyzing both binomial (accuracy) and continuous (reaction time) repeated measurements. OUTCOMES & RESULTS: The LMEM analysis reveals that both spelling accuracy and reaction time improved and, for accuracy, improved significantly more quickly under a training schedule with distributed, compared to clustered, practice. We present guidance on obtaining and interpreting various effect sizes and measures of statistical significance from LMEM, and include a simulation study comparing two p-value methods for generalized LMEM. CONCLUSION: We provide a strong case for the application of LMEM to the analysis of training studies as a preferable alternative to visual analysis or other statistical techniques. When applied to a treatment dataset, the evidence supports that the approach holds up under the extreme conditions of small numbers of individuals, with repeated measures training data for both continuous (reaction time) and binomially distributed (accuracy) dependent measures. The approach provides standardized measures of effect sizes that are obtained through readily available and well-supported statistical packages, and provides statistically rigorous estimates of the expected average effect size of training effects, taking into account variability across both items and individuals.

From complexity to distinctiveness: The effect of expertise on letter perception.

Fluent, adult readers of alphabetic languages encounter hundreds of millions of individual letters. What is the impact of such extensive experience on the perception and identification of letters? Recent evidence indicates that expert and naïve observers perceive letters differently. Here, we focus on the relationship between expertise and letter complexity (number of visual features) and distinctiveness (overlap in features with the other letters of the alphabet). Using a same-different letter judgement task, we examined the performance of individuals with high levels of expertise with Roman letters, but with different amounts of experience with the Arabic alphabet. The results reveal a trade-off between letter complexity and distinctiveness, such that while naïve individuals are sensitive only to letter complexity and not distinctiveness, the opposite is true for individuals with high expertise with an alphabet. These findings reveal a learning trajectory in which, with increasing experience, the influence of letter complexity is supplanted by distinctiveness, which requires an understanding of the relationship of each letter to the other possible letter shapes in the alphabet as a whole.