Predictive Coding and Internal Error Correction in Speech Production.

Speech production involves the careful orchestration of sophisticated systems, yet overt speech errors rarely occur under naturalistic conditions. The present functional magnetic resonance imaging study sought neural evidence for internal error detection and correction by leveraging a tongue twister paradigm that induces the potential for speech errors while excluding any overt errors from analysis. Previous work using the same paradigm in the context of silently articulated and imagined speech production tasks has demonstrated forward predictive signals in auditory cortex during speech and presented suggestive evidence of internal error correction in left posterior middle temporal gyrus (pMTG) on the basis that this area tended toward showing a stronger response when potential speech errors are biased toward nonwords compared to words (Okada et al., 2018). The present study built on this prior work by attempting to replicate the forward prediction and lexicality effects in nearly twice as many participants but introduced novel stimuli designed to further tax internal error correction and detection mechanisms by biasing speech errors toward taboo words. The forward prediction effect was replicated. While no evidence was found for a significant difference in brain response as a function of lexical status of the potential speech error, biasing potential errors toward taboo words elicited significantly greater response in left pMTG than biasing errors toward (neutral) words. Other brain areas showed preferential response for taboo words as well but responded below baseline and were less likely to reflect language processing as indicated by a decoding analysis, implicating left pMTG in internal error correction.

Human peripheral blood mononuclear cells enriched in endothelial progenitor cells via quality and quantity controlled culture accelerate vascularization and wound healing in a porcine wound model.

The transplantation of endothelial progenitor cells (EPCs) is used to promote wound angiogenesis. In patients with chronic wounds and accompanying morbidities, EPCs are often compromised in number and function. To overcome these limitations, we previously developed a quality and quantity controlled (QQ) culture system to enrich peripheral blood mononuclear cells (PBMNCs) in EPCs. To evaluate the wound healing efficacy of mononuclear cells (MNCs) harvested after QQ culture (QQMNCs), preclinical studies were performed on large animals. MNCs harvested from the blood of healthy human subjects were cultured in the presence of angiogenic cytokines and growth factors in a serum-free medium for 7 days. A total of 5 × 106 QQMNCs per full-thickness skin defect or control saline was injected into wounds induced in cyclosporine-immunosuppressed pigs. EPC colony-forming assays revealed a significantly higher number of definitive (partially differentiated) EPC colony-forming units in QQMNCs. Flow cytometry evaluation of QQMNC surface markers showed enrichment of CD34+ and CD133+ stem cell populations, significant reduction in CCR2+ cell percentages, and a greater than 10-fold increase in the percentage of anti-inflammatory M2-type macrophages (CD206+ cells) compared with PBMNCs. Wounds treated with QQMNCs had a significantly higher closure rate. Wounds were harvested, frozen, and sectioned at day 21 postoperatively. Hematoxylin and eosin staining revealed that the epithelization of QQMNC-treated wounds was more advanced than in controls. Treated wounds developed granulation tissue with more mature collagen and larger capillary networks. CD31 and human mitochondrial co-staining confirmed the presence of differentiated human cells within newly formed vessels. Real-time polymerase chain reaction (PCR) showed upregulation of interleukin 6 (IL-6), IL-10, and IL-4 in the wound bed, suggesting paracrine activity of the transplanted QQMNCs. Our data demonstrate for the first time that QQ culture of MNCs obtained from a small amount of peripheral blood yields vasculogenic and therapeutic cells effective in wound healing.

Phonological Feature Repetition Suppression in the Left Inferior Frontal Gyrus.

Models of speech production posit a role for the motor system, predominantly the posterior inferior frontal gyrus, in encoding complex phonological representations for speech production, at the phonemic, syllable, and word levels [Roelofs, A. A dorsal-pathway account of aphasic language production: The WEAVER++/ARC model. Cortex, 59(Suppl. C), 33-48, 2014; Hickok, G. Computational neuroanatomy of speech production. Nature Reviews Neuroscience, 13, 135-145, 2012; Guenther, F. H. Cortical interactions underlying the production of speech sounds. Journal of Communication Disorders, 39, 350-365, 2006]. However, phonological theory posits subphonemic units of representation, namely phonological features [Chomsky, N., & Halle, M. The sound pattern of English, 1968; Jakobson, R., Fant, G., & Halle, M. Preliminaries to speech analysis. The distinctive features and their correlates. Cambridge, MA: MIT Press, 1951], that specify independent articulatory parameters of speech sounds, such as place and manner of articulation. Therefore, motor brain systems may also incorporate phonological features into speech production planning units. Here, we add support for such a role with an fMRI experiment of word sequence production using a phonemic similarity manipulation. We adapted and modified the experimental paradigm of Oppenheim and Dell [Oppenheim, G. M., & Dell, G. S. Inner speech slips exhibit lexical bias, but not the phonemic similarity effect. Cognition, 106, 528-537, 2008; Oppenheim, G. M., & Dell, G. S. Motor movement matters: The flexible abstractness of inner speech. Memory & Cognition, 38, 1147-1160, 2010]. Participants silently articulated words cued by sequential visual presentation that varied in degree of phonological feature overlap in consonant onset position: high overlap (two shared phonological features; e.g., /r/ and /l/) or low overlap (one shared phonological feature, e.g., /r/ and /b/). We found a significant repetition suppression effect in the left posterior inferior frontal gyrus, with increased activation for phonologically dissimilar words compared with similar words. These results suggest that phonemes, particularly phonological features, are part of the planning units of the motor speech system.

Human Peripheral Blood Mononuclear Cells Incubated in Vasculogenic Conditioning Medium Dramatically Improve Ischemia/Reperfusion Acute Kidney Injury in Mice.

Acute kidney injury (AKI) is a major clinical problem that still has no established treatment. We investigated the efficacy of cultured human peripheral blood mononuclear cells (PBMNCs) for AKI. Ischemia/reperfusion injury (IRI) was used to induce AKI in male nonobese diabetic (NOD/severe combined immunodeficiency) mice aged 7 to 8 wk. PBMNCs were isolated from healthy volunteers and were subjected to quality and quantity controlled (QQc) culture for 7 d in medium containing stem cell factor, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin 6. IRI-induced mice were divided into 3 groups and administered (1) 1 × 106 PBMNCs after QQc culture (QQc PBMNCs group), (2) 1 × 106 PBMNCs without QQc culture (non-QQc PBMNCs group), or (3) vehicle without PBMNCs (IRI control group). PBMNCs were injected via the tail vein 24 h after induction of IRI, followed by assessment of renal function, histological changes, and homing of injected cells. Blood urea nitrogen and serum creatinine (Cr) 72 h after induction of IRI in the QQc PBMNCs group dramatically improved compared with those in the IRI control and the non-QQc PBMNCs groups, accompanied by the improvement of tubular damages. Interstitial fibrosis 14 d after induction of IRI was also significantly improved in the QQc PBMNCs group compared with the other groups. The renoprotective effect noted in the QQc PBMNCs group was accompanied by reduction of peritubular capillary loss. The change of PBMNCs' population (increase of CD34+ cells, CD133+ cells, and CD206+ cells) and increased endothelial progenitor cell colony-forming potential by QQc culture might be one of the beneficial mechanisms for restoring AKI. In conclusion, an injection of human QQc PBMNCs 24 h after induction of IRI dramatically improved AKI in mice.

Neural evidence for predictive coding in auditory cortex during speech production.

Recent models of speech production suggest that motor commands generate forward predictions of the auditory consequences of those commands, that these forward predications can be used to monitor and correct speech output, and that this system is hierarchically organized (Hickok, Houde, & Rong, Neuron, 69(3), 407--422, 2011; Pickering & Garrod, Behavior and Brain Sciences, 36(4), 329--347, 2013). Recent psycholinguistic research has shown that internally generated speech (i.e., imagined speech) produces different types of errors than does overt speech (Oppenheim & Dell, Cognition, 106(1), 528--537, 2008; Oppenheim & Dell, Memory & Cognition, 38(8), 1147-1160, 2010). These studies suggest that articulated speech might involve predictive coding at additional levels than imagined speech. The current fMRI experiment investigates neural evidence of predictive coding in speech production. Twenty-four participants from UC Irvine were recruited for the study. Participants were scanned while they were visually presented with a sequence of words that they reproduced in sync with a visual metronome. On each trial, they were cued to either silently articulate the sequence or to imagine the sequence without overt articulation. As expected, silent articulation and imagined speech both engaged a left hemisphere network previously implicated in speech production. A contrast of silent articulation with imagined speech revealed greater activation for articulated speech in inferior frontal cortex, premotor cortex and the insula in the left hemisphere, consistent with greater articulatory load. Although both conditions were silent, this contrast also produced significantly greater activation in auditory cortex in dorsal superior temporal gyrus in both hemispheres. We suggest that these activations reflect forward predictions arising from additional levels of the perceptual/motor hierarchy that are involved in monitoring the intended speech output.

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice.

Persistent inflammatory environment and abnormal macrophage activation are characteristics of chronic diabetic wounds. Here, we attempted to characterize the differences in macrophage activation and temporal variations in cytokine expression in diabetic and non-diabetic wounds, with a focus on interleukin (IL)-6 mRNA expression and the p38 MAPK and PI3K/Akt signaling pathways. Cutaneous wound closure, CD68- and arginase-1 (Arg-1)-expressing macrophages, and cytokine mRNA expression were examined in non-diabetic and streptozotocin-induced type 1 diabetic mice at different time points after injury. The effect of IL-6 on p38 MAPK and Akt phosphorylation was investigated, and an in vitro scratch assay was performed to determine the role of IL-6 in primary skin fibroblast migration. Before injury, mRNA expression levels of the inflammatory markers iNOS, IL-6, and TNF-α were higher in diabetic mice; however, IL-6 expression was significantly lower 6 h post injury in diabetic wounds than that in non-diabetic wounds. Non-diabetic wounds exhibited increased p38 MAPK and Akt phosphorylation; however, no such increase was found in diabetic wounds. In fibroblasts from non-diabetic mice, IL-6 increased the phosphorylation of p38 MAPK and levels of its downstream factor CREB, and also significantly increased Akt phosphorylation and levels of its upstream factor P13K. These effects of IL-6 were not detected in fibroblasts derived from the diabetic mice. In scratch assays, IL-6 stimulated the migration of primary cultured skin fibroblasts from the non-diabetic mice, and the inhibition of p38 MAPK was found to markedly suppress IL-6-stimulated fibroblast migration. These findings underscore the critical differences between diabetic and non-diabetic wounds in terms of macrophage activation, cytokine mRNA expression profile, and involvement of the IL-6-stimulated p38 MAPK-Akt signaling pathway. Aberrant macrophage activation and abnormalities in the cytokine mRNA expression profile during different phases of wound healing should be addressed when designing effective therapeutic modalities for refractory diabetic wounds.

An fMRI study of perception and action in deaf signers.

Since the discovery of mirror neurons, there has been a great deal of interest in understanding the relationship between perception and action, and the role of the human mirror system in language comprehension and production. Two questions have dominated research. One concerns the role of Broca's area in speech perception. The other concerns the role of the motor system more broadly in understanding action-related language. The current study investigates both of these questions in a way that bridges research on language with research on manual actions. We studied the neural basis of observing and executing American Sign Language (ASL) object and action signs. In an fMRI experiment, deaf signers produced signs depicting actions and objects as well as observed/comprehended signs of actions and objects. Different patterns of activation were found for observation and execution although with overlap in Broca's area, providing prima facie support for the claim that the motor system participates in language perception. In contrast, we found no evidence that action related signs differentially involved the motor system compared to object related signs. These findings are discussed in the context of lesion studies of sign language execution and observation. In this broader context, we conclude that the activation in Broca's area during ASL observation is not causally related to sign language understanding.

An fMRI Study of Audiovisual Speech Perception Reveals Multisensory Interactions in Auditory Cortex.

Research on the neural basis of speech-reading implicates a network of auditory language regions involving inferior frontal cortex, premotor cortex and sites along superior temporal cortex. In audiovisual speech studies, neural activity is consistently reported in posterior superior temporal Sulcus (pSTS) and this site has been implicated in multimodal integration. Traditionally, multisensory interactions are considered high-level processing that engages heteromodal association cortices (such as STS). Recent work, however, challenges this notion and suggests that multisensory interactions may occur in low-level unimodal sensory cortices. While previous audiovisual speech studies demonstrate that high-level multisensory interactions occur in pSTS, what remains unclear is how early in the processing hierarchy these multisensory interactions may occur. The goal of the present fMRI experiment is to investigate how visual speech can influence activity in auditory cortex above and beyond its response to auditory speech. In an audiovisual speech experiment, subjects were presented with auditory speech with and without congruent visual input. Holding the auditory stimulus constant across the experiment, we investigated how the addition of visual speech influences activity in auditory cortex. We demonstrate that congruent visual speech increases the activity in auditory cortex.

The Effect of Control-released Basic Fibroblast Growth Factor in Wound Healing: Histological Analyses and Clinical Application.

BACKGROUND: Basic fibroblast growth factors (bFGFs) play a crucial role in wound healing by promoting fibroblast proliferation and neovascularization. However, drawback of bFGF is short half-life in free form. Gelatin has a capability of sustaining growth factors, which are gradually released while degradation. The purpose of this study is to see whether bFGF-impregnated gelatin sheet is effective in a murine model and whether it could also be available for patients in a safe manner. METHODS: Full-thickness skin defect was created on C57BL/6J mice and covered with bFGF with gelatin sheet (group A), bFGF without gelatin sheet (group B), phosphate buffer saline (PBS) with gelatin sheet (group C), and only PBS (group D). Wound healing was evaluated in terms of percent wound closure, granulation thickness, wound maturity, and vascular density. Clinical trial was conducted for patients who received either acute or chronic ulcers. The sheets were put onto the wounds and covered by hydrocolloid dressing, which was changed weekly. RESULTS: Groups A and B exhibited better wound healing than groups C and D in all aspects. Moreover, group A showed better results than group B at day 7 in terms of wound closure, collagen maturity, and vascularity. Efficacy without any adverse events was found in the clinical series. CONCLUSIONS: These findings suggest that control-released bFGF using gelatin sheet is effective for promoting wound healing. Such therapeutic strategy was considered to offer several clinical advantages including rapid healing and reduction of the dressing change with less patient discomfort.

Comparison of the neural correlates of retrieval success in tests of cued recall and recognition memory.

The neural correlates of successful retrieval on tests of word stem recall and recognition memory were compared. In the recall test, subjects viewed word stems, half of which were associated with studied items and half with unstudied items, and for each stem attempted to recall a corresponding study word. In the recognition test, old/new judgments were made on old and new words. The neural correlates of successful retrieval were identified by contrasting activity elicited by correctly endorsed test items. Old > new effects common to the two tasks were found in medial and lateral parietal and right entorhinal cortex. Common new > old effects were identified in medial and left frontal cortex, and left anterior intra-parietal sulcus. Greater old > new effects were evident for cued recall in inferior parietal regions abutting those demonstrating common effects, whereas larger new > old effects were found for recall in left frontal cortex and the anterior cingulate. New > old effects were also found for the recall task in right lateral anterior prefrontal cortex, where they were accompanied by old > new effects during recognition. It is concluded that successful recall and recognition are associated with enhanced activity in a common set of recollection-sensitive parietal regions, and that the greater activation in these regions during recall reflects the greater dependence of that task on recollection. Larger new > old effects during recall are interpreted as reflections of the greater opportunity for iterative retrieval attempts when retrieval cues are partial rather than copy cues.

Conduction aphasia, sensory-motor integration, and phonological short-term memory - an aggregate analysis of lesion and fMRI data.

Conduction aphasia is a language disorder characterized by frequent speech errors, impaired verbatim repetition, a deficit in phonological short-term memory, and naming difficulties in the presence of otherwise fluent and grammatical speech output. While traditional models of conduction aphasia have typically implicated white matter pathways, recent advances in lesions reconstruction methodology applied to groups of patients have implicated left temporoparietal zones. Parallel work using functional magnetic resonance imaging (fMRI) has pinpointed a region in the posterior most portion of the left planum temporale, area Spt, which is critical for phonological working memory. Here we show that the region of maximal lesion overlap in a sample of 14 patients with conduction aphasia perfectly circumscribes area Spt, as defined in an aggregate fMRI analysis of 105 subjects performing a phonological working memory task. We provide a review of the evidence supporting the idea that Spt is an interface site for the integration of sensory and vocal tract-related motor representations of complex sound sequences, such as speech and music and show how the symptoms of conduction aphasia can be explained by damage to this system.

Word or word-like? Dissociating orthographic typicality from lexicality in the left occipito-temporal cortex.

Prior lesion and functional imaging studies have highlighted the importance of the left ventral occipito-temporal (LvOT) cortex for visual word recognition. Within this area, there is a posterior-anterior hierarchy of subregions that are specialized for different stages of orthographic processing. The aim of the present fMRI study was to dissociate the effects of subword orthographic typicality (e.g., cider [high] vs. cynic [low]) from the effect of lexicality (e.g., pollen [word] vs. pillen [pseudoword]). We therefore orthogonally manipulated the orthographic typicality of written words and pseudowords (nonwords and pseudohomophones) in a visual lexical decision task. Consistent with previous studies, we identified greater activation for pseudowords than words (i.e., an effect of lexicality) in posterior LvOT cortex. In addition, we revealed higher activation for atypical than typical strings, irrespective of lexicality, in a left inferior occipital region that is posterior to LvOT cortex. When lexical decisions were made more difficult in the context of pseudohomophone foils, left anterior temporal activation also increased for atypical relative to typical strings. The latter finding agrees with the behavior of patients with progressive anterior temporal lobe degeneration, who have particular difficulty recognizing words with atypical orthography. The most novel outcome of this study is that, within a distributed network of regions supporting orthographic processing, we have identified a left inferior occipital region that is particularly sensitive to the typicality of subword orthographic patterns.

Hierarchical organization of human auditory cortex: evidence from acoustic invariance in the response to intelligible speech.

Hierarchical organization of human auditory cortex has been inferred from functional imaging observations that core regions respond to simple stimuli (tones) whereas downstream regions are selectively responsive to more complex stimuli (band-pass noise, speech). It is assumed that core regions code low-level features, which are combined at higher levels in the auditory system to yield more abstract neural codes. However, this hypothesis has not been critically evaluated in the auditory domain. We assessed sensitivity to acoustic variation within intelligible versus unintelligible speech using functional magnetic resonance imaging and a multivariate pattern analysis. Core auditory regions on the dorsal plane of the superior temporal gyrus exhibited high levels of sensitivity to acoustic features, whereas downstream auditory regions in both anterior superior temporal sulcus and posterior superior temporal sulcus (pSTS) bilaterally showed greater sensitivity to whether speech was intelligible or not and less sensitivity to acoustic variation (acoustic invariance). Acoustic invariance was most pronounced in more pSTS regions of both hemispheres, which we argue support phonological level representations. This finding provides direct evidence for a hierarchical organization of human auditory cortex and clarifies the cortical pathways supporting the processing of intelligible speech.

Two cortical mechanisms support the integration of visual and auditory speech: a hypothesis and preliminary data.

Visual speech (lip-reading) influences the perception of heard speech. The literature suggests at least two possible mechanisms for this influence: "direct" sensory-sensory interaction, whereby sensory signals from auditory and visual modalities are integrated directly, likely in the superior temporal sulcus, and "indirect" sensory-motor interaction, whereby visual speech is first mapped onto motor-speech representations in the frontal lobe, which in turn influences sensory perception via sensory-motor integration networks. We hypothesize that both mechanisms exist, and further that previous demonstrations of lip-reading functional activations in Broca's region and the posterior planum temporale reflect the sensory-motor mechanism. We tested one prediction of this hypothesis using fMRI. We assessed whether viewing visual speech (contrasted with facial gestures) activates the same network as a speech sensory-motor integration task (listen to and then silently rehearse speech). Both tasks activated locations within Broca's area, dorsal premotor cortex, and the posterior planum temporal (Spt), and focal regions of the STS, all of which have previously been implicated in sensory-motor integration for speech. This finding is consistent with the view that visual speech influences heard speech via sensory-motor networks. Lip-reading also activated a much wider network in the superior temporal lobe than the sensory-motor task, possibly reflecting a more direct cross-sensory integration network.

Area Spt in the human planum temporale supports sensory-motor integration for speech processing.

Processing incoming sensory information and transforming this input into appropriate motor responses is a critical and ongoing aspect of our moment-to-moment interaction with the environment. While the neural mechanisms in the posterior parietal cortex (PPC) that support the transformation of sensory inputs into simple eye or limb movements has received a great deal of empirical attention-in part because these processes are easy to study in nonhuman primates-little work has been done on sensory-motor transformations in the domain of speech. Here we used functional magnetic resonance imaging and multivariate analysis techniques to demonstrate that a region of the planum temporale (Spt) shows distinct spatial activation patterns during sensory and motor aspects of a speech task. This result suggests that just as the PPC supports sensorimotor integration for eye and limb movements, area Spt forms part of a sensory-motor integration circuit for the vocal tract.

Identification of lexical-phonological networks in the superior temporal sulcus using functional magnetic resonance imaging.

General agreement exists that dorsal aspects of the temporal lobe support the perception of speech but there is less agreement regarding the mapping between levels of speech processing and neural regions within the dorsal temporal lobe. The present experiment sought to identify temporal lobe regions that support one such level, namely, lexical-phonological representation/processing. To do this, we manipulated phonological neighborhood density, a variable that affects processing within lexical-phonological networks. In a functional magnetic resonance imaging experiment, 10 participants listened to blocks of either high-density or low-density words. High-density words produced significantly more activation in the posterior half of the superior temporal sulcus bilaterally, suggesting that these regions are involved in lexical-phonological processing networks.

Left posterior auditory-related cortices participate both in speech perception and speech production: Neural overlap revealed by fMRI.

Recent neuroimaging studies and neuropsychological data suggest that there are regions in posterior auditory cortex that participate both in speech perception and speech production. An outstanding question is whether the same neural regions support both perception and production or whether there exist discrete cortical fields subserving these functions. Previous neurophysiological studies suggest that there is indeed regional overlap between these systems, but those studies used a rehearsal task to assess production. The present study addressed this question in an event-related fMRI experiment in which subjects listened to speech and in separate trials, performed a covert object naming task. Single subject analysis revealed regions of coactivation for speech perception and production in the left posterior superior temporal sulcus (pSTS), left area Spt (a region in the Sylvian fissure at the parietal-temporal boundary), and left inferior frontal gyrus. These results are consistent with lesion data and previous physiological data indicating that posterior auditory cortex plays a role in both reception and expression of speech. We discuss these findings within the context of a neuroanatomical framework that proposes these neural sites are a part of an auditory-motor integration system.

Human cortical auditory motion areas are not motion selective.

The existence of a specialized mechanism supporting auditory motion processing in humans is a matter of debate in the psychophysical literature. Recent functional neuroimaging data appear to have resolved the debate in favor of a specialized motion system in that several studies have found cortical regions that seem to be motion selective. While all these studies contrast some form of moving auditory stimulation with a stationary stimulus, none have adequately controlled for the possibility that these areas are simply computing sound-source location and not motion per se: a moving stimulus varies in spatial location as well as motion, and so a system computing spatial location (and not motion) would be activated in response to both a moving and stationary sound source. To control for this possibility, ten subjects were scanned while listening to moving stimuli and while listening to stationary stimuli that varied randomly in spatial location. Consistent with previous imaging studies, we found that a motion stimulus when contrasted with rest (scanner noise) activated STG/planum temporale (bilaterally) and right parietal lobe. However, stationary stimuli presented at varying locations activated these regions equally well, arguing against the existence of specialized motion-processing areas in human cortex.

Word length modulates neural activity in auditory cortex during covert object naming.

Several lines of evidence show that posterior portions of left auditory cortex participate in aspects of speech production. A current hypothesis is that these regions play a specific role in processing phonological codes. We used event-related fMRI to test this hypothesis. Subjects covertly named objects that had names varying in length from one to four syllables. Behavioral data, both in previous work and in the present study, show an increase in naming reaction time as words get longer, reflecting the increase in phonological load. If left posterior auditory areas participate in phonological aspects of production, word length should modulate neural activity in this region. Object naming activated the left planum temporale in each subject, confirming previous findings of auditory cortex involvement in speech production. The timecourse of activation in this region showed a length effect, consistent with its hypothesized role in phonological processing. Similar effects were also observed in premotor cortex, but not in occipital-temporal cortex, which presumably supports visual processing of the pictures to be named.