Semantic Categorization of Naming Responses Based on Prearticulatory Electrical Brain Activity.

PURPOSE: Object naming requires visual decoding, conceptualization, semantic categorization, and phonological encoding, all within 400 to 600 ms of stimulus presentation and before a word is spoken. In this study, we sought to predict semantic categories of naming responses based on prearticulatory brain activity recorded with scalp EEG in healthy individuals. METHODS: We assessed 19 healthy individuals who completed a naming task while undergoing EEG. The naming task consisted of 120 drawings of animate/inanimate objects or abstract drawings. We applied a one-dimensional, two-layer, neural network to predict the semantic categories of naming responses based on prearticulatory brain activity. RESULTS: Classifications of animate, inanimate, and abstract responses had an average accuracy of 80%, sensitivity of 72%, and specificity of 87% across participants. Across participants, time points with the highest average weights were between 470 and 490 milliseconds after stimulus presentation, and electrodes with the highest weights were located over the left and right frontal brain areas. CONCLUSIONS: Scalp EEG can be successfully used in predicting naming responses through prearticulatory brain activity. Interparticipant variability in feature weights suggests that individualized models are necessary for highest accuracy. Our findings may inform future applications of EEG in reconstructing speech for individuals with and without speech impairments.

Normative Values for Word Syllable Duration With Interpretation in a Large Sample of Stroke Survivors With Aphasia.

PURPOSE: Slow speech rate and abnormal temporal prosody are primary diagnostic criteria for differentiating between people with aphasia who do and do not have apraxia of speech. We sought to identify appropriate cutoff values for abnormal word syllable duration (WSD) in a word repetition task, interpret them relative to a data set of people with chronic aphasia, and evaluate the extent to which manually derived measures could be approximated through an automated process that relied on commercial speech recognition technology. METHOD: Fifty neurotypical participants produced 49 multisyllabic words during a repetition task. Audio recordings were submitted to an automated speech recognition (ASR) service (IBM Watson) to measure word duration and generate an orthographic transcription. The transcribed words were compared to a lexical database, and the number of syllables was identified. Automatic and manual measures were compared for 50% of the sample. Results were interpreted relative to WSD scores from an existing data set of 195 people with mostly chronic aphasia. RESULTS: ASR correctly identified 83% of target words and 98% of target syllable counts. Automated word duration calculations were longer than manual measures due to imprecise cursor placement. Upon applying regression coefficients to the automated measures and examining the frequency distributions for both manual and estimated measures, a WSD of 303-316 ms was found to indicate longer-than-normal performance (corresponding to the 95th percentile). With this cutoff, 40%-45% of participants with aphasia in our comparison sample had an abnormally long WSD. CONCLUSIONS: We recommend using a rounded WSD cutoff score between 303 and 316 ms for manual measures. Future research will focus on customizing automated WSD methods to speech samples from people with aphasia, identifying target words that maximize production and measurement reliability, and developing WSD standard scores based on a large participant sample with and without aphasia.

Neural network bases of thematic semantic processing in language production.

Semantic processing is a central component of language and cognition. The anterior temporal lobe is postulated to be a key hub for semantic processing, but the posterior temporoparietal cortex is also involved in thematic associations during language. It is possible that these regions act in concert and depend on an anteroposterior network linking the temporal pole with posterior structures to support thematic semantic processing during language production. We employed connectome-based lesion-symptom mapping to examine the causal relationship between lesioned white matter pathways and thematic processing language deficits among individuals with post-stroke aphasia. Seventy-nine adults with chronic aphasia completed the Philadelphia Naming Test, and semantic errors were coded as either thematic or taxonomic to control for taxonomic errors. Controlling for nonverbal conceptual-semantic knowledge as measured by the Pyramids and Palm Trees Test, lesion size, and the taxonomic error rate, thematic error rate was associated with loss of white matter connections from the temporal pole traversing in peri-Sylvian regions to the posterior cingulate and the insula. These findings support the existence of a distributed network underlying thematic relationship processing in language as opposed to discrete cortical areas.

Electrophysiologic evidence of reorganization in poststroke aphasia.

Electrophysiologic methods have been used to investigate neural changes in individuals with poststroke aphasia. The major types of electrophysiologic measures include the event-related potential (ERP) and spectral power, and aspects of both (including amplitude, topography, and power) have been shown to differ in people with aphasia. Not only that, these measures are sensitive to spontaneous and treatment-induced language change. The purpose of this chapter is to review evidence of poststroke reorganization in the language network that has been identified in the acute and chronic phases of poststroke aphasia. The chapter will begin with a brief introduction to electrophysiologic methods and then focus on evidence from the most commonly studied ERPs and spectral bands in aphasia.

Language Recovery after Brain Injury: A Structural Network Control Theory Study.

Aphasia recovery after stroke depends on the condition of the remaining, extralesional brain network. Network control theory (NCT) provides a unique, quantitative approach to assess the interaction between brain networks. In this longitudinal, large-scale, whole-brain connectome study, we evaluated whether controllability measures of language-related regions are associated with treated aphasia recovery. Using probabilistic tractography and controlling for the effects of structural lesions, we reconstructed whole-brain diffusion tensor imaging (DTI) connectomes from 68 individuals (20 female, 48 male) with chronic poststroke aphasia who completed a three-week language therapy. Applying principles of NCT, we computed regional (1) average and (2) modal controllability, which decode the ability of a region to (1) spread control input through the brain network and (2) to facilitate brain state transitions. We tested the relationship between pretreatment controllability measures of 20 language-related left hemisphere regions and improvements in naming six months after language therapy using multiple linear regressions and a parsimonious elastic net regression model with cross-validation. Regional controllability of the inferior frontal gyrus (IFG) pars opercularis, pars orbitalis, and the anterior insula were associated with treatment outcomes independently of baseline aphasia severity, lesion volume, age, education, and network size. Modal controllability of the IFG pars opercularis was the strongest predictor of treated aphasia recovery with cross-validation and outperformed traditional graph theory, lesion load, and demographic measures. Regional NCT measures can reflect the status of the residual language network and its interaction with the remaining brain network, being able to predict language recovery after aphasia treatment.SIGNIFICANCE STATEMENT Predicting and understanding language recovery after brain injury remains a challenging, albeit a fundamental aspect of human neurology and neuroscience. In this study, we applied network control theory (NCT) to fully harness the concept of brain networks as dynamic systems and to evaluate their interaction. We studied 68 stroke survivors with aphasia who underwent imaging and longitudinal behavioral assessments coupled with language therapy. We found that the controllability of the inferior frontal regional network significantly predicted recovery in language production six months after treatment. Importantly, controllability outperformed traditional demographic, lesion, and graph-theoretical measures. Our findings shed light on the neurobiological basis of human language and can be translated into personalized rehabilitation approaches.

Demystifying the Complexity of Aphasia Treatment: Application of the Rehabilitation Treatment Specification Systemx.

A considerable body of research supports the use of behavioral communication treatment as the standard of care for aphasia. In spite of robust progress in clinical aphasiology, many questions regarding optimal care remain unanswered. One of the major challenges to progress in the field is the lack of a common framework to adequately describe individual treatments, which, if available, would allow comparisons across studies as well as improved communication among researchers, clinicians, and other stakeholders. Here, we describe how aphasia treatment approaches can be systematically characterized using the Rehabilitation Treatment Specification System (RTSS). At the core of the RTSS is a tripartite structure that focuses on targets (the behavior that is expected to change as a result of treatment), ingredients (what a clinician does to affect change in the target), and mechanism(s) of action (why a given treatment works by linking the ingredients to the target). Three separate articles in the current issue specifically describe how the RTSS can be used to describe different kinds of aphasia treatment approaches: functional approaches, cognitive-linguistic approaches, and biological approaches. It is our hope that the application of the RTSS in clinical aphasiology will improve communication in published studies, grant proposals, and in the clinical care of persons with aphasia.

Defining the Neurobiological Mechanisms of Action in Aphasia Therapies: Applying the Rehabilitation Treatment Specification System Framework to Research and Practice in Aphasia.

The Rehabilitation Treatment Specification System (RTSS) was developed as a systematic way to describe rehabilitation treatments for the purpose of both research and practice. The RTSS groups treatments by type and describes them by 3 elements: the treatment (1) ingredients and (2) the mechanisms of action that yield changes in the (3) target behavior. Adopting the RTSS has the potential to improve consistency in research, allowing for better cross-study comparisons to strengthen the body of research supporting various treatments. Because it is still early in its development, the RTSS has not yet been widely implemented across different rehabilitation disciplines. In particular, aphasia recovery is one area of rehabilitation that could benefit from a unifying framework. Accordingly, this article is part of a series where we illustrate how the RTSS can be applied to aphasia treatment and research. This article more specifically focuses on examining the neurobiological mechanisms of action associated with experimental aphasia therapies, including brain stimulation and pharmacologic intervention, as well as more traditional behavioral therapy. Key elements of the RTSS are described, and 4 example studies are used to illustrate how the RTSS can be implemented. The benefits of a unifying framework for the future of aphasia treatment research and practice are discussed.

Cortical microstructural changes associated with treated aphasia recovery.

OBJECTIVES: To investigate the hypothesis that language recovery in post-stroke aphasia is associated with structural brain changes. METHODS: We evaluated whether treatment-induced improvement in naming is associated with reorganization of tissue microstructure within residual cortical regions. To this end, we performed a retrospective longitudinal treatment study using comprehensive language-linguistic assessments and diffusion MRI sequences optimized for the assessment of complex microstructure (diffusional kurtosis imaging) to evaluate the relationship between language treatment response and cortical changes in 26 individuals with chronic stroke-induced aphasia. We employed elastic net statistical models controlling for baseline factors including age, sex, and time since the stroke, as well as lesion volume. RESULTS: We observed that improved naming accuracy (Philadelphia Naming Test) was statistically associated with increased post-treatment microstructural integrity in the left posterior superior temporal gyrus. Moreover, increase in microstructural integrity in the left middle temporal gyrus and left inferior temporal gyrus was specifically associated with a decrease in semantic paraphasias. This longitudinal relationship between brain tissue integrity and language improvement was not observed in other non-language related brain regions. INTERPRETATION: Our findings provide evidence that structural brain changes in the preserved left hemisphere regions are associated with treatment-induced language recovery in aphasia and are part of the mechanisms supporting language and brain injury recovery.

Topological signal processing and inference of event-related potential response.

BACKGROUND: Topological signal processing is a novel approach for decoding multiscale features of signals recorded through electroencephalography (EEG) based on topological data analysis (TDA). New method: We establish stability properties of the TDA descriptor persistence landscape (PL) in event-related potential (ERP) across multi-trial EEG signals, state algorithms for computing PL, and propose an exact inference framework on persistence and PLs. RESULTS: We apply the topological signal processing and inference framework to compare ERPs between individuals with post-stroke aphasia and healthy controls under a speech altered auditory feedback (AAF) paradigm. Results show significant PL difference in the ERP response of aphasic individuals and healthy controls over the parietal-occipital and occipital regions with respect to speech onset, and no significant PL difference in any regions with respect to the two pitch-shift stimuli. Comparison with existing methods: In comparison, spatial patterns of difference between aphasic individuals and healthy controls by persistence, local variance, and spectral powers are much more diffuse than the PL patterns. In simulation results, the exact test on persistence and PLs has more robust performance than the baseline tests on local variance and spectral powers. CONCLUSIONS: Persistence features provide a more robust EEG marker than local variance, and spectral powers. It could be a potentially powerful tool for comparing electrophysiological correlates in neurological disorders.

Indirect White Matter Pathways Are Associated With Treated Naming Improvement in Aphasia.

BACKGROUND: White matter disconnection of language-specific brain regions associates with worse aphasia recovery. Despite a loss of direct connections, many stroke survivors may maintain indirect connections between brain regions. OBJECTIVE: To determine (1) whether preserved direct connections between language-specific brain regions relate to better poststroke naming treatment outcomes compared to no direct connections and (2) whether for individuals with a loss of direct connections, preserved indirect connections are associated with better treatment outcomes compared to individuals with no connections. METHODS: We computed structural whole-brain connectomes from 69 individuals with chronic left-hemisphere stroke and aphasia who completed a 3-week-long language treatment that was supplemented by either anodal transcranial direct current stimulation (A-tDCS) or sham stimulation (S-tDCS). We determined differences in naming improvement between individuals with direct, indirect, and no connections using 1-way analyses of covariance and multivariable linear regressions. RESULTS: Independently of tDCS modality, direct or indirect connections between the inferior frontal gyrus pars opercularis and angular gyrus were both associated with a greater increase in correct naming compared to no connections (P = .027 and P = .039, respectively). Participants with direct connections between the inferior frontal gyrus pars opercularis and middle temporal gyrus who received S-tDCS and participants with indirect connections who received A-tDCS significantly improved in naming accuracy. CONCLUSIONS: Poststroke preservation of indirect white matter connections is associated with better treated naming improvement in aphasia even when direct connections are damaged. This mechanistic information can be used to stratify and predict treated naming recovery in individuals with aphasia.

Slowed Compensation Responses to Altered Auditory Feedback in Post-Stroke Aphasia: Implications for Speech Sensorimotor Integration.

Developing a clearer understanding of impairments that underlie the behavioral characteristics of aphasia is essential for the development of targeted treatments and will help inform theories of speech motor control. Impairments in sensorimotor integration of speech in individuals with conduction aphasia have previously been implicated in their repetition deficits. However, much less is known about the extent to which these integrative deficits occur outside of conduction aphasia and how this manifests behaviorally in areas other than speech repetition. In this study, we aimed to address these issues by examining the behavioral correlates of speech sensorimotor impairment under altered auditory feedback (AAF) and their relationship with the impaired ability to independently correct for online errors during picture naming in people with aphasia. We found that people with aphasia generate slower vocal compensation response to pitch-shift AAF stimuli compared with controls. However, when the timing of responses was controlled for, no significant difference in the magnitude of vocal pitch compensation was observed between aphasia and control groups. Moreover, no relationship was found between self-correction of naming errors and the timing and magnitude of vocal compensation responses to AAF. These findings suggest that slowed compensation is a potential behavioral marker of impaired sensorimotor integration in aphasia.

Novel Colchicine Derivatives and their Anti-cancer Activity.

In this paper we provide an overview of the status of various colchicine derivatives in preclinical development with special focus on their anti-cancer activity. We discuss several groups of compounds that have been designed to differentially bind with specific affinities for tubulin ß isotypes, especially in regard to ßIII, which is commonly over-expressed in cancer. Computational prediction, protein-based and cell-based assays are summarized as well as some animal tests conducted on these compounds. It is concluded that an untapped potential exists for exploiting the colchicine scaffold as a pharmacophore with the possibility of increasing its affinity for tubulin isotypes overexpressed in cancer and decreasing it for normal cells thereby widening the therapeutic window.

Nucleoside transporter gene expression in wild-type and mENT1 knockout mice.

Owing to the overlapping and redundant roles of the seven mammalian nucleoside transporters (NTs), which belong to two protein families (ENTs and CNTs), the physiological importance of individual NTs has been difficult to assess. Mice that have NT genes knocked out can be a valuable tool in gaining an understanding of the NT proteins. We have generated a strain of mice that is homozygous for a disruption mutation between exons 2 and 3 of the mouse equilibrative nucleoside transporter, mENT1. We have undertaken a quantitative survey of NT gene expression in 10 tissues, as well as microarray analysis of heart and kidney, from wild-type and mENT1 knockout mice. Rather than a consistent change in expression of NT genes in all tissues of mENT1 knockout mice, a complex pattern of changes was found. Some genes, such as those encoding mCNT1 and mCNT3 in colon tissue, exhibited increased expression, whereas other genes, such as those encoding mCNT2 and mENT4 in lung tissue, exhibited decreased expression. Although mCNT3 has been shown to be important in human and rat kidney tissue, we were unable to detect mCNT3 transcripts in the kidney of either the wild-type or mENT1 knockout mice, suggesting differences in renal nucleoside resorption between species.

Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives.

BACKGROUND: A maximum entropy approach is proposed to predict the cytotoxic effects of a panel of colchicine derivatives in several human cancer cell lines. Data was obtained from cytotoxicity assays performed with 21 drug molecules from the same family of colchicine compounds and correlate these results with independent tubulin isoform expression measurements for several cancer cell lines. The maximum entropy method is then used in conjunction with computed relative binding energy values for each of the drug molecules against tubulin isotypes to which these compounds bind with different affinities. RESULTS: We have found by using our analysis that alphabetaI and alphabetaIII tubulin isoforms are the most important isoforms in establishing predictive response of cancer cell sensitivity to colchicine derivatives. However, since alphabetaI tubulin is widely distributed in the human body, targeting it would lead to severe adverse side effects. Consequently, we have identified tubulin isotype alphabetaIII as the most important molecular target for inhibition of microtubule polymerization and hence cancer cell cytotoxicity. Tubulin isotypes alphabetaI and alphabetaII are concluded to be secondary targets. CONCLUSIONS: The benefit of being able to correlate expression levels of specific tubulin isotypes and the resultant cell death effect is that it will enable us to better understand the origin of drug resistance and hence design optimal structures for the elimination of cancer cells. The conclusion of the study described herein identifies tubulin isotype alphabetaIII as a target for optimized chemotherapy drug design.

Computational design and biological testing of highly cytotoxic colchicine ring A modifications.

Microtubules are the primary target for many anti-cancer drugs, the majority of which bind specifically to beta-tubulin. The existence of several beta-tubulin isotypes, coupled with their varied expression in normal and cancerous cells provides a platform upon which to construct selective chemotherapeutic agents. We have examined five prevalent human beta-tubulin isotypes and identified the colchicine-binding site as the most promising for drug design based on specificity. Using this binding site as a template, we have designed several colchicine derivatives and computationally probed them for affinity to the beta-tubulin isotypes. These compounds were synthesized and subjected to cytotoxicity assays to determine their effectiveness against several cancerous cell lines. We observed a correlation between computational-binding predictions and experimentally determined IC(50) values, demonstrating the utility of computational screening in the design of more effective colchicine derivatives. The most promising derivative exhibited an IC(50) approximately threefold lower than values previously reported for either colchicine or paclitaxel, demonstrating the utility of computational design and assessment of binding to tubulin.

Class III beta-tubulin is a marker of paclitaxel resistance in carcinomas of unknown primary site.

PURPOSE: In this study, we determine the prevalence and the prognostic value of the class III beta-tubulin microtubule protein examined immunohistochemically, in tumors of 40 patients with carcinomas of unknown primary site treated with paclitaxel-based chemotherapy. METHODS: Immunohistochemical intensity of staining and percentage of cells were quantified. Clinical characteristics, response to chemotherapy, progression-free survival, and overall survival were assessed for relationships with the expression of class III beta-tubulin. RESULTS: The response rate was 17.9% (seven partial responses among 39 valuable patients), while eleven patients had a stable disease (28.2%) and 21 patients progressed on therapy (53.8%). Patients with high class III beta-tubulin expression were more resistant to taxane-based chemotherapy, defined as progression under treatment, while patient characteristics were not found to be correlated with response to chemotherapy. Patients whose tumors expressed high levels of class III beta-tubulin isotype had shorter overall survival, while there was a trend for an association with progression free survival. Multivariate analysis showed that class III beta-tubulin expression was independently correlated with progression free survival and overall survival. CONCLUSIONS: These findings suggest that a high level of expression of class III beta-tubulin in tumor cells is associated with resistance to paclitaxel and decreased survival in patients with carcinomas of unknown primary receiving paclitaxel-based chemotherapy.

Effects of exercise training on antitumor efficacy of doxorubicin in MDA-MB-231 breast cancer xenografts.

PURPOSE: Exercise is becoming readily accepted as a beneficial adjunct therapy to maintain or enhance quality of life in breast cancer patients undergoing adjuvant chemotherapy. An essential precursor to these studies is to investigate whether exercise modulates the antitumor efficacy of chemotherapeutic agents. EXPERIMENTAL DESIGN: Athymic female mice were transplanted with MDA-MB-231 breast xenografts and randomly assigned to one of four groups (n = 21 per group): (a) control, (b) exercise-only, (c) doxorubicin-only, or (d) exercise + doxorubicin. Exercise groups performed progressive treadmill running up to 18 m/min at 0% grade for 45 minutes, 5 d/wk for 8 weeks. RESULTS: Tumor growth delay was significantly longer in the doxorubicin-only and exercise + doxorubicin groups compared with the control (median 42 versus 25 days, P = 0.0082; 36 versus 25 days, P = 0.029, respectively) and exercise-only groups (median 42 versus 25 days, P = 0.029; 36 versus 25 days, P = 0.080, respectively). There was no significant difference between the doxorubicin-only and exercise + doxorubicin groups (median 42 versus 36 days, P = 0.33), suggesting that moderate intensity exercise does not significantly influence doxorubicin-induced tumor growth delay. CONCLUSION: These studies are essential to fully understand the safety and application of exercise as a supportive intervention in cancer control.