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Research over the past several decades has revealed that non-linguistic cognitive impairments can appear alongside language deficits in individuals with aphasia. One vulnerable cognitive domain is executive function, an umbrella term for the higher-level cognitive processes that allow us to direct our behavior towards a goal. Studies in healthy adults reveal that executive function abilities are supported by inner speech, the ability to use language silently in one's head. Therefore, inner speech may mediate the connection between language and executive function deficits in individuals with aphasia. Here, we investigated whether inner speech ability may link language and cognitive impairments in 59 adults with chronic, post-stroke aphasia. We used two approaches to measure inner speech: one based on internal retrieval of words and one based on internal retrieval plus silent manipulation of the retrieved phonological forms. Then, we examined relationships between these two approaches to measuring inner speech and five aspects of executive function ability: response inhibition, conflict monitoring/resolution, general task-switching ability, phonological control, and semantic control. We also looked for dissociations between inner speech ability and executive function ability. Our results show tentative relationships between inner speech (across multiple measurement approaches) and all aspects of executive function except for response inhibition. We also found evidence for a double dissociation: many participants show intact executive function despite poor inner speech, and vice versa, so neither process is strictly reliant on the other. We suggest that this work provides preliminary evidence of a bidirectional relationship between inner speech and executive function: inner speech supports some aspects of executive function via internal self-cueing and certain aspects of executive function support performance on complex inner speech tasks.

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Despite the many mistakes we make while speaking, people can effectively communicate because we monitor our speech errors. However, the cognitive abilities and brain structures that support speech error monitoring are unclear. There may be different abilities and brain regions that support monitoring phonological speech errors versus monitoring semantic speech errors. We investigated speech, language, and cognitive control abilities that relate to detecting phonological and semantic speech errors in 41 individuals with aphasia who underwent detailed cognitive testing. Then, we used support vector regression lesion symptom mapping to identify brain regions supporting detection of phonological versus semantic errors in a group of 76 individuals with aphasia. The results revealed that motor speech deficits as well as lesions to the ventral motor cortex were related to reduced detection of phonological errors relative to semantic errors. Detection of semantic errors selectively related to auditory word comprehension deficits. Across all error types, poor cognitive control related to reduced detection. We conclude that monitoring of phonological and semantic errors relies on distinct cognitive abilities and brain regions. Furthermore, we identified cognitive control as a shared cognitive basis for monitoring all types of speech errors. These findings refine and expand our understanding of the neurocognitive basis of speech error monitoring.

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People use cognitive control across many contexts in daily life, yet it remains unclear how cognitive control is used in contexts involving language. Distinguishing language-specific cognitive control components may be critical to understanding aphasia, which can co-occur with cognitive control deficits. For example, deficits in control of semantic representations (i.e., semantic control), are thought to contribute to semantic deficits in aphasia. Conversely, little is known about control of phonological representations (i.e., phonological control) in aphasia. We developed a switching task to investigate semantic and phonological control in 32 left hemisphere stroke survivors with aphasia and 37 matched controls. We found that phonological and semantic control were related, but dissociate in the presence of switching demands. People with aphasia exhibited group-wise impairment at phonological control, although individual impairments were subtle except in one case. Several individuals with aphasia exhibited frank semantic control impairments, and these individuals had relative deficits on other semantic tasks. The present findings distinguish semantic control from phonological control, and confirm that semantic control impairments contribute to semantic deficits in aphasia.

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Optimal performance in any task relies on the ability to detect and correct errors. The anterior cingulate cortex and the broader posterior medial frontal cortex (pMFC) are active during error processing. However, it is unclear whether damage to the pMFC impairs error monitoring. We hypothesized that successful error monitoring critically relies on connections between the pMFC and broader cortical networks involved in executive functions and the task being monitored. We tested this hypothesis in the context of speech error monitoring in people with post-stroke aphasia. Diffusion weighted images were collected in 51 adults with chronic left-hemisphere stroke and 37 age-matched control participants. Whole-brain connectomes were derived using constrained spherical deconvolution and anatomically-constrained probabilistic tractography. Support vector regressions identified white matter connections in which lost integrity in stroke survivors related to reduced error detection during confrontation naming. Lesioned connections to the bilateral pMFC were related to reduce error monitoring, including many connections to regions associated with speech production and executive function. We conclude that connections to the pMFC support error monitoring. Error monitoring in speech production is supported by the structural connectivity between the pMFC and regions involved in speech production, comprehension, and executive function. Interactions between pMFC and other task-relevant processors may similarly be critical for error monitoring in other task contexts.

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Anosognosia, or lack of self-awareness, is often present following neurological injury and can result in poor functional outcomes. The specific phenomenon of intellectual awareness, the knowledge that a function is impaired in oneself, has not been widely studied in post-stroke aphasia. We aim to identify behavioral and neural correlates of intellectual awareness by comparing stroke survivors' self-reports of anomia to objective naming performance and examining lesion sites. Fifty-three participants with chronic aphasia without severe comprehension deficits rated their naming ability and completed a battery of behavioral tests. We calculated the reliability and accuracy of participant self-ratings, then examined the relationship of poor intellectual awareness to speech, language, and cognitive measures. We used support vector regression lesion-symptom mapping (SVR-LSM) to determine lesion locations associated with impaired and preserved intellectual awareness. Reliability and accuracy of self-ratings varied across the participants. Poor intellectual awareness was associated with reduced performance on tasks that rely on semantics. Our SVR-LSM results demonstrated that anterior inferior frontal lesions were associated with poor awareness, while mid-superior temporal lesions were associated with preserved awareness. An anterior-posterior gradient was evident in the unthresholded lesion-symptom maps. While many people with chronic aphasia and relatively intact comprehension can accurately and reliably report the severity of their anomia, others overestimate, underestimate, or inconsistently estimate their naming abilities. Clinicians should consider this when administering self-rating scales, particularly when semantic deficits or anterior inferior frontal lesions are present. Administering self-ratings on multiple days may be useful to check the reliability of patient perceptions.

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Methods to precisely control growth factor presentation in a local and sustained fashion are of increasing interest for a number of complex tissue engineering applications. The cytokine transforming growth factor beta (TGFß) plays a key role in promoting the chondrogenic differentiation of human mesenchymal stem cells (hMSCs). Traditional chondrogenic approaches utilize soluble delivery, an approach with limited application for clinical translation. In this work, we introduce a reactive thiol onto TGFß and covalently tether the growth factor into poly(ethylene glycol) (PEG) hydrogels using a photoinitiated thiol-acrylate polymerization mechanism. We demonstrate the bioactivity of thiolated TGFß, before and after polymerization, using a SMAD2 reporter cell line. hMSCs were encapsulated in PEG hydrogels with and without tethered TGFß, and subsequently assayed for glycosaminoglycan and collagen II production as indicators of chondrogenesis. Over a 21-day time course, tethered TGFß promoted chondrogenesis at levels similar to a positive control using solubly dosed growth factor. These results provide evidence that tethered TGFß materials can be successfully used to promote chondrogenic differentiation of MSCs.

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Photoinitiated polymerization remains a robust method for fabrication of hydrogels, as these reactions allow facile spatial and temporal control of gelation and high compatibility for encapsulation of cells and biologics. The chain-growth reaction of macromolecular monomers, such as acrylated PEG and hyaluronan, is commonly used to form hydrogels, but there is growing interest in step-growth photopolymerizations, such as the thiol-ene "click" reaction, as an alternative. Thiol-ene reactions are not susceptible to oxygen inhibition and rapidly form hydrogels using low initiator concentrations. In this work, we characterize the differences in recovery of bioactive proteins when exposed to similar photoinitiation conditions during thiol-ene versus acrylate polymerizations. Following exposure to chain polymerization of acrylates, lysozyme bioactivity was approximately 50%; after step-growth thiol-ene reaction, lysozyme retained nearly 100% of its prereaction activity. Bioactive protein recovery was enhanced 1000-fold in the presence of a thiol-ene reaction, relative to recovery from solutions containing identical primary radical concentrations, but without the thiol-ene components. When the cytokine TGFß was encapsulated in PEG hydrogels formed via the thiol-ene reaction, full protein bioactivity was preserved.

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Transforming growth factor beta (TGFß(1)) influences a host of cellular fates, including proliferation, migration, and differentiation. Due to its short half-life and cross reactivity with a variety of cells, clinical application of TGFß(1) may benefit from a localized delivery strategy. Photoencapsulation of proteins in polymeric matrices offers such an opportunity; however, the reactions forming polymer networks often result in lowered protein bioactivity. Here, PEG-based gels formed from the chain polymerization of acrylated monomers were studied as a model system for TGFß(1) delivery. Concentrations of acrylate group ranging from 0 to 50 mM and photopolymerization conditions were systematically altered to study their effects on TGFß(1) bioactivity. In addition, two peptide sequences, WSHW (K(D) = 8.20 nM) and KRIWFIPRSSWY (K(D) = 10.41 nM), that exhibit binding affinity for TGFß(1) were introduced into the monomer solution prior to encapsulation to determine if affinity binders would increase the activity and release of the encapsulated growth factor. The addition of affinity peptides enhanced the bioactivity of TGFß(1) in vitro from 1.3- to 2.9-fold, compared to hydrogels with no peptide. Further, increasing the concentration of affinity peptides by a factor of 100-10000 relative to the TGFß(1) concentration increased fractional recovery of the protein from PEG hydrogels.

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We report the first use of a polymerization-based ELISA substrate solution employing enzymatically mediated radical polymerization as a dual-mode amplification strategy. Enzymes are selectively coupled to surfaces to generate radicals that subsequently lead to polymerization-based amplification (PBA) and biodetection. Sensitivity and amplification of the polymerization-based detection system were optimized in a microwell strip format using a biotinylated microwell surface with a glucose oxidase (GOx)-avidin conjugate. The immobilized GOx is used to initiate polymerization, enabling the detection of the biorecognition event visually or through the use of a plate reader. Assay response is compared to that of an enzymatic substrate utilizing nitroblue tetrazolium in a simplified assay using biotinylated wells. The polymerization substrate exhibits equivalent sensitivity (2 µg/mL of GOx-avidin) and over three times greater signal amplification than this traditional enzymatic substrate since each radical that is enzymatically generated leads to a large number of polymerization events. Enzyme-mediated polymerization proceeds in an ambient atmosphere without the need for external energy sources, which is an improvement upon previous PBA platforms. Substrate formulations are highly sensitive to both glucose and iron concentrations at the lowest enzyme concentrations. Increases in amplification time correspond to higher assay sensitivities with no increase in non-specific signal. Finally, the polymerization substrate generated a signal to noise ratio of 14 at the detection limit (156 ng/mL) in an assay of transforming growth factor-beta.

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