Intensive speech and language therapy in patients with chronic aphasia after stroke: a randomised, open-label, blinded-endpoint, controlled trial in a health-care setting.

BACKGROUND: Treatment guidelines for aphasia recommend intensive speech and language therapy for chronic (≥6 months) aphasia after stroke, but large-scale, class 1 randomised controlled trials on treatment effectiveness are scarce. We aimed to examine whether 3 weeks of intensive speech and language therapy under routine clinical conditions improved verbal communication in daily-life situations in people with chronic aphasia after stroke. METHODS: In this multicentre, parallel group, superiority, open-label, blinded-endpoint, randomised controlled trial, patients aged 70 years or younger with aphasia after stroke lasting for 6 months or more were recruited from 19 inpatient or outpatient rehabilitation centres in Germany. An external biostatistician used a computer-generated permuted block randomisation method, stratified by treatment centre, to randomly assign participants to either 3 weeks or more of intensive speech and language therapy (≥10 h per week) or 3 weeks deferral of intensive speech and language therapy. The primary endpoint was between-group difference in the change in verbal communication effectiveness in everyday life scenarios (Amsterdam-Nijmegen Everyday Language Test A-scale) from baseline to immediately after 3 weeks of treatment or treatment deferral. All analyses were done using the modified intention-to-treat population (those who received 1 day or more of intensive treatment or treatment deferral). This study is registered with ClinicalTrials.gov, number NCT01540383. FINDINGS: We randomly assigned 158 patients between April 1, 2012, and May 31, 2014. The modified intention-to-treat population comprised 156 patients (78 per group). Verbal communication was significantly improved from baseline to after intensive speech and language treatment (mean difference 2·61 points [SD 4·94]; 95% CI 1·49 to 3·72), but not from baseline to after treatment deferral (-0·03 points [4·04]; -0·94 to 0·88; between-group difference Cohen's d 0·58; p=0·0004). Eight patients had adverse events during therapy or treatment deferral (one car accident [in the control group], two common cold [one patient per group], three gastrointestinal or cardiac symptoms [all intervention group], two recurrent stroke [one in intervention group before initiation of treatment, and one before group assignment had occurred]); all were unrelated to study participation. INTERPRETATION: 3 weeks of intensive speech and language therapy significantly enhanced verbal communication in people aged 70 years or younger with chronic aphasia after stroke, providing an effective evidence-based treatment approach in this population. Future studies should examine the minimum treatment intensity required for meaningful treatment effects, and determine whether treatment effects cumulate over repeated intervention periods. FUNDING: German Federal Ministry of Education and Research and the German Society for Aphasia Research and Treatment.

The novel language-systematic aphasia screening SAPS: screening-based therapy in combination with computerised home training.

BACKGROUND: SAPS-'Sprachsystematisches Aphasiescreening'-is a novel language-systematic aphasia screening developed for the German language, which already had been positively evaluated. It offers a fast assessment of modality-specific psycholinguistic components at different levels of complexity and the derivation of impairment-based treatment foci from the individual performance profile. However, SAPS has not yet been evaluated in combination with the new SAPS-based treatment. AIMS: To replicate the practicality of SAPS and to investigate the effectiveness of a SAPS-based face-to-face therapy combined with computerised home training in a feasibility study. To examine the soundness of the treatment design, to determine treatment-induced changes in patient performance as measured by SAPS, to assess parallel changes in communicative abilities, and to differentiate therapy effects achieved by face-to-face therapy versus add-on effects achieved by later home training. METHODS & PROCEDURES: Sixteen participants with post-stroke aphasia (PWAs) were included into the study. They were administered the SAPS and communicative testing before and after the treatment regimen. Each PWA received one therapy session followed by home training per day, with the individual treatment foci being determined according to initial SAPS profile, and duration of treatment and possible change of focus dependent on performance assessed by continuous therapy monitoring. OUTCOMES & RESULTS: The combination of therapy and home training based on the SAPS was effective for all participants. We showed significant improvements for impairment-based SAPS performance and, with high inter-individual variability, in everyday communication. These two main targets of speech and language therapy were correlated and SAPS improvements after therapy were significantly higher than after home training. CONCLUSIONS & IMPLICATIONS: SAPS offers the assessment of an individual performance profile in order to derive sufficiently diversified, well-founded and specific treatment foci and to follow up changes in performance. The appending treatment regimen has shown to be effective for our participants. Thus, the study revealed feasibility of our approach.

Crystal Structures of the Human Doublecortin C- and N-terminal Domains in Complex with Specific Antibodies.

Doublecortin is a microtubule-associated protein produced during neurogenesis. The protein stabilizes microtubules and stimulates their polymerization, which allows migration of immature neurons to their designated location in the brain. Mutations in the gene that impair doublecortin function and cause severe brain formation disorders are located on a tandem repeat of two doublecortin domains. The molecular mechanism of action of doublecortin is only incompletely understood. Anti-doublecortin antibodies, such as the rabbit polyclonal Abcam 18732, are widely used as neurogenesis markers. Here, we report the generation and characterization of antibodies that bind to single doublecortin domains. The antibodies were used as tools to obtain structures of both domains. Four independent crystal structures of the N-terminal domain reveal several distinct open and closed conformations of the peptide linking N- and C-terminal domains, which can be related to doublecortin function. An NMR assignment and a crystal structure in complex with a camelid antibody fragment show that the doublecortin C-terminal domain adopts the same well defined ubiquitin-like fold as the N-terminal domain, despite its reported aggregation and molten globule-like properties. The antibodies' unique domain specificity also renders them ideal research tools to better understand the role of individual domains in doublecortin function. A single chain camelid antibody fragment specific for the C-terminal doublecortin domain affected microtubule binding, whereas a monoclonal mouse antibody specific for the N-terminal domain did not. Together with steric considerations, this suggests that the microtubule-interacting doublecortin domain observed in cryo-electron micrographs is the C-terminal domain rather than the N-terminal one.

Real-time monitoring of binding events on a thermostabilized human A2A receptor embedded in a lipid bilayer by surface plasmon resonance.

Membrane proteins (MPs) are prevalent drug discovery targets involved in many cell processes. Despite their high potential as drug targets, the study of MPs has been hindered by limitations in expression, purification and stabilization in order to acquire thermodynamic and kinetic parameters of small molecules binding. These bottlenecks are grounded on the mandatory use of detergents to isolate and extract MPs from the cell plasma membrane and the coexistence of multiple conformations, which reflects biochemical versatility and intrinsic instability of MPs. In this work ,we set out to define a new strategy to enable surface plasmon resonance (SPR) measurements on a thermostabilized and truncated version of the human adenosine (A2A) G-protein-coupled receptor (GPCR) inserted in a lipid bilayer nanodisc in a label- and detergent-free manner by using a combination of affinity tags and GFP-based fluorescence techniques. We were able to detect and characterize small molecules binding kinetics on a GPCR fully embedded in a lipid environment. By providing a comparison between different binding assays in membranes, nanodiscs and detergent micelles, we show that nanodiscs can be used for small molecule binding studies by SPR to enhance the MP stability and to trigger a more native-like behaviour when compared to kinetics on A2A receptors isolated in detergent. This work provides thus a new methodology in drug discovery to characterize the binding kinetics of small molecule ligands for MPs targets in a lipid environment.

Therapy-induced brain reorganization patterns in aphasia.

Both hemispheres are engaged in recovery from word production deficits in aphasia. Lexical therapy has been shown to induce brain reorganization even in patients with chronic aphasia. However, the interplay of factors influencing reorganization patterns still remains unresolved. We were especially interested in the relation between lesion site, therapy-induced recovery, and beneficial reorganization patterns. Thus, we applied intensive lexical therapy, which was evaluated with functional magnetic resonance imaging, to 14 chronic patients with aphasic word retrieval deficits. In a group study, we aimed to illuminate brain reorganization of the naming network in comparison with healthy controls. Moreover, we intended to analyse the data with joint independent component analysis to relate lesion sites to therapy-induced brain reorganization, and to correlate resulting components with therapy gain. As a result, we found peri-lesional and contralateral activations basically overlapping with premorbid naming networks observed in healthy subjects. Reduced activation patterns for patients compared to controls before training comprised damaged left hemisphere language areas, right precentral and superior temporal gyrus, as well as left caudate and anterior cingulate cortex. There were decreasing activations of bilateral visuo-cognitive, articulatory, attention, and language areas due to therapy, with stronger decreases for patients in right middle temporal gyrus/superior temporal sulcus, bilateral precuneus as well as left anterior cingulate cortex and caudate. The joint independent component analysis revealed three components indexing lesion subtypes that were associated with patient-specific recovery patterns. Activation decreases (i) of an extended frontal lesion disconnecting language pathways occurred in left inferior frontal gyrus; (ii) of a small frontal lesion were found in bilateral inferior frontal gyrus; and (iii) of a large temporo-parietal lesion occurred in bilateral inferior frontal gyrus and contralateral superior temporal gyrus. All components revealed increases in prefrontal areas. One component was negatively correlated with therapy gain. Therapy was associated exclusively with activation decreases, which could mainly be attributed to higher processing efficiency within the naming network. In our joint independent component analysis, all three lesion patterns disclosed involved deactivation of left inferior frontal gyrus. Moreover, we found evidence for increased demands on control processes. As expected, we saw partly differential reorganization profiles depending on lesion patterns. There was no compensatory deactivation for the large left inferior frontal lesion, with its less advantageous outcome probably being related to its disconnection from crucial language processing pathways.

Elucidation of direct competition and allosteric modulation of small-molecular-weight protein ligands using surface plasmon resonance methods.

The present work introduces a surface plasmon resonance-based method for the discrimination of direct competition and allosteric effects that occur in ternary systems comprising a receptor protein and two small-molecular-weight ligands that bind to it. Fatty acid binding protein 4, fructose-1,6-bisphosphatase and human serum albumin were used as model receptor molecules to demonstrate the performance of the method. For each of the receptor molecules, pairs of ligand molecules were selected for which either direct competition or an allosteric effect had already been determined by other methods. The method of discrimination introduced here is based on the surface plasmon resonance responses observed at equilibrium when an immobilized receptor protein is brought into contact with binary mixtures of interacting ligands. These experimentally determined responses are compared with the responses calculated using a theoretical model that considers both direct competition and allosteric ligand interaction modes. This study demonstrates that the allosteric ternary complex model, which enables calculation of the fractional occupancy of the protein by each ligand in such ternary systems, is well suited for the theoretical calculation of these types of responses. For all of the ternary systems considered in this work, the experimental and calculated responses in the chosen concentration ratio range were identical within a five-σ confidence interval when the calculations considered the correct interaction mode of the ligands (direct competition or different types of allosteric regulation), and in case of allosteric modulation, also the correct strength of this effect. This study also demonstrates that the allosteric ternary complex model-based calculations are well suited to predict the ideal concentration ratio range or even single concentration ratios that can serve as hot spots for discrimination, and such hot spots can drastically reduce the numbers of measurements needed for discrimination between direct competition and distinct modulation modes (neutral, positive or negative allostery).

Add-on Effects of Repetitive Transcranial Magnetic Stimulation on Subacute Aphasia Therapy: Enhanced Improvement of Functional Communication and Basic Linguistic Skills. A Randomized Controlled Study.

OBJECTIVE: To determine to what extent repetitive transcranial magnetic stimulation (rTMS) combined with speech and language therapy improves functional communication and basic linguistic skills of individuals with subacute aphasia. DESIGN: Randomized, blinded, and sham-controlled study. SETTING: Neurologic rehabilitation hospital. PARTICIPANTS: Participants (N=30) with subacute aphasia after stroke. INTERVENTIONS: During a 2-week treatment period, half of the participants received 10 sessions of 20-minute inhibitory 1-Hz rTMS over the right inferior frontal gyrus (Brodmann area 45), and the other half received sham stimulation. Directly thereafter, all the participants underwent 45 minutes of speech and language therapy. MAIN OUTCOME MEASURES: Aachen Aphasia Test, Amsterdam-Nijmegen Everyday Language Test (ANELT), a naming screening, and subscales of the FIM, all assessed the day before and the day after treatment period. RESULTS: The participants who received real rTMS significantly improved with respect to all 10 measures of basic linguistic skills and functional communication, whereas sham-treated participants significantly improved in only 6 of 10 measures (paired t tests, P<.05). There was a significant difference in the gains made by the 2 groups on 5 of 10 measures including functional communication (ANELT) (repeated-measures analysis of variance, P≤.05). CONCLUSIONS: For the first time, this study has demonstrated that basic linguistic skills as well as functional communication are bolstered by combining rTMS and behavioral language therapy in patients with subacute aphasia.

Paving the way for speech: voice-training-induced plasticity in chronic aphasia and apraxia of speech--three single cases.

Difficulties with temporal coordination or sequencing of speech movements are frequently reported in aphasia patients with concomitant apraxia of speech (AOS). Our major objective was to investigate the effects of specific rhythmic-melodic voice training on brain activation of those patients. Three patients with severe chronic nonfluent aphasia and AOS were included in this study. Before and after therapy, patients underwent the same fMRI procedure as 30 healthy control subjects in our prestudy, which investigated the neural substrates of sung vowel changes in untrained rhythm sequences. A main finding was that post-minus pretreatment imaging data yielded significant perilesional activations in all patients for example, in the left superior temporal gyrus, whereas the reverse subtraction revealed either no significant activation or right hemisphere activation. Likewise, pre- and posttreatment assessments of patients' vocal rhythm production, language, and speech motor performance yielded significant improvements for all patients. Our results suggest that changes in brain activation due to the applied training might indicate specific processes of reorganization, for example, improved temporal sequencing of sublexical speech components. In this context, a training that focuses on rhythmic singing with differently demanding complexity levels as concerns motor and cognitive capabilities seems to support paving the way for speech.

An eye movement based reading intervention in lexical and segmental readers with acquired dyslexia.

Due to their brain damage, aphasic patients with acquired dyslexia often rely to a greater extent on lexical or segmental reading procedures. Thus, therapy intervention is mostly targeted on the more impaired reading strategy. In the present work we introduce a novel therapy approach based on real-time measurement of patients' eye movements as they attempt to read words. More specifically, an eye movement contingent technique of stepwise letter de-masking was used to support sequential reading, whereas fixation-dependent initial masking of non-central letters stimulated a lexical (parallel) reading strategy. Four lexical and four segmental readers with acquired central dyslexia received our intensive reading intervention. All participants showed remarkable improvements as evident in reduced total reading time, a reduced number of fixations per word and improved reading accuracy. Both types of intervention led to item-specific training effects in all subjects. A generalisation to untrained items was only found in segmental readers after the lexical training. Eye movement analyses were also used to compare word processing before and after therapy, indicating that all patients, with one exclusion, maintained their preferred reading strategy. However, in several cases the balance between sequential and lexical processing became less extreme, indicating a more effective individual interplay of both word processing routes.

Success rates of intensive aphasia therapy: real-world data from 448 patients between 2003 and 2020.

BACKGROUND: Aphasia is a devastating consequence after stroke, affecting millions of patients each year. Studies have shown that intensive speech and language therapy (SLT) is effective in the chronic phase of aphasia. Leveraging a large single-center cohort of persons with aphasia (PWA) including patients also in the subacute phase, we assessed treatment effects of intensive aphasia therapy in a real-world setting. METHODS: Data were collected at the Aachen aphasia ward in Germany between 2003 and 2020. Immediate treatment responses across different language domains were assessed with the Aachen Aphasia Test (AAT) using single-case psychometrics, conducted before and after 6-7 weeks of intensive SLT (10 h per week, median (IQR) dosage = 68 (61-76)). We adjusted for spontaneous recovery in subacute patients. Differential treatment effects between subgroups of chronicity and predictors of therapy response were investigated. RESULTS: A total of 448 PWA were included (29% female, median (IQR) age = 54 (46-62) years, median (IQR) time post-onset = 11 (6-20) months) with 12% in the early subacute, 15% in the late subacute and 74% in the chronic phase of aphasia. The immediate responder rate was 59%. Significant improvements in all AAT subtests und subscales were observed hinting at broad effectiveness across language domains. The degree of therapy-induced improvement did not differ between the chronicity groups. Time post-onset, dosage of therapy and aphasia severity at the beginning of treatment were predictors of immediate treatment response. DISCUSSION: Intensive therapy protocols for aphasia after stroke are yielding substantial responder rates in a routine clinical setting including a wide range of patients.

Mapping the conformational space accessible to BACE2 using surface mutants and cocrystals with Fab fragments, Fynomers and Xaperones.

The aspartic protease BACE2 is responsible for the shedding of the transmembrane protein Tmem27 from the surface of pancreatic ß-cells, which leads to inactivation of the ß-cell proliferating activity of Tmem27. This role of BACE2 in the control of ß-cell maintenance suggests BACE2 as a drug target for diabetes. Inhibition of BACE2 has recently been shown to lead to improved control of glucose homeostasis and to increased insulin levels in insulin-resistant mice. BACE2 has 52% sequence identity to the well studied Alzheimer's disease target enzyme ß-secretase (BACE1). High-resolution BACE2 structures would contribute significantly to the investigation of this enzyme as either a drug target or anti-target. Surface mutagenesis, BACE2-binding antibody Fab fragments, single-domain camelid antibody VHH fragments (Xaperones) and Fyn-kinase-derived SH3 domains (Fynomers) were used as crystallization helpers to obtain the first high-resolution structures of BACE2. Eight crystal structures in six different packing environments define an ensemble of low-energy conformations available to the enzyme. Here, the different strategies used for raising and selecting BACE2 binders for cocrystallization are described and the crystallization success, crystal quality and the time and resources needed to obtain suitable crystals are compared.

Recovery in a letter-by-letter reader: more efficiency at the expense of normal reading strategy.

Although changes in reading performance of recovering letter-by-letter readers have been described in some detail, no prior research has provided an in-depth analysis of the underlying adaptive word processing strategies. Our work examined the reading performance of a letter-by-letter reader, FH, over a period of 15 months, using eye movement methodology to delineate the recovery process at two different time points (T1, T2). A central question is whether recovery is characterized either by moving back towards normal word processing or by refinement and possibly automatization of an existing pathological strategy that was developed in response to the impairment. More specifically, we hypothesized that letter-by-letter reading may be executed with at least four different strategies and our work sought to distinguish between these alternatives. During recovery significant improvements in reading performance were achieved. A shift of fixation positions from the far left to the extreme right of target words was combined with many small and very few longer regressive saccades. Apparently, 'letter-by-letter reading' took the form of local clustering, most likely corresponding to the formation of sublexical units of analysis. This pattern was more pronounced at T2, suggesting that improvements in reading efficiency may come at the expense of making it harder to eventually return to normal reading.

From a concept to a word in a syntactically complete sentence: an fMRI study on spontaneous language production in an overt picture description task.

Spontaneous language has rarely been subjected to neuroimaging studies. This study therefore introduces a newly developed method for the analysis of linguistic phenomena observed in continuous language production during fMRI. Most neuroimaging studies investigating language have so far focussed on single word or - to a smaller extent - sentence processing, mostly due to methodological considerations. Natural language production, however, is far more than the mere combination of words to larger units. Therefore, the present study aimed at relating brain activation to linguistic phenomena like word-finding difficulties or syntactic completeness in a continuous language fMRI paradigm. A picture description task with special constraints was used to provoke hesitation phenomena and speech errors. The transcribed speech sample was segmented into events of one second and each event was assigned to one category of a complex schema especially developed for this purpose. The main results were: conceptual planning engages bilateral activation of the precuneus. Successful lexical retrieval is accompanied - particularly in comparison to unsolved word-finding difficulties - by the left middle and superior temporal gyrus. Syntactic completeness is reflected in activation of the left inferior frontal gyrus (IFG) (area 44). In sum, the method has proven to be useful for investigating the neural correlates of lexical and syntactic phenomena in an overt picture description task. This opens up new prospects for the analysis of spontaneous language production during fMRI.

The influence of emotional associations on the neural correlates of semantic priming.

Emotions influence our everyday life in several ways. With the present study, we wanted to examine the impact of emotional information on neural correlates of semantic priming, a well-established technique to investigate semantic processing. Stimuli were presented with a short SOA of 200 ms as subjects performed a lexical decision task during fMRI measurement. Seven experimental conditions were compared: positive/negative/neutral related, positive/negative/neutral unrelated, nonwords (all words were nouns). Behavioral data revealed a valence specific semantic priming effect (i.e., unrelated > related) only for neutral and positive related word pairs. On a neural level, the comparison of emotional over neutral relations showed activation in left anterior medial frontal cortex, superior frontal gyrus, and posterior cingulate. Interactions for the different relations were located in left anterior part of the medial frontal cortex, cingulate regions, and right hippocampus (positive > neutral + negative) and left posterior part of medial frontal cortex (negative > neutral + positive). The results showed that emotional information have an influence on semantic association processes. While positive and neutral information seem to share a semantic network, negative relations might induce compensatory mechanisms that inhibit the spread of activation between related concepts. The neural correlates highlighted a distributed neural network, primarily involving attention, memory and emotion related processing areas in medial fronto-parietal cortices. The differentiation between anterior (positive) and posterior part (negative) of the medial frontal cortex was linked to the type of affective manipulation with more cognitive demands being involved in the automatic processing of negative information.

Combining biophysical screening and X-ray crystallography for fragment-based drug discovery.

Over the past decade, fragment-based drug discovery (FBDD) has gained importance for the generation of novel ideas to inspire synthetic chemistry. In order to identify small molecules that bind to a target protein, multiple approaches have been utilized by various groups in the pharmaceutical industry and by academic groups. The combination of fragment screening by biophysical methods and in particular with surface plasmon resonance technologies (SPR) together with the visualization of the binding properties by X-ray crystallography offers a number of benefits. Screening by SPR identifies ligands for a target protein as well as provides an assessment of the binding properties with respect to affinity, stoichiometry, and specificity of the interaction. Despite the huge technology advances of the past years, X-ray crystallography is still a resource-intensive technology, and SPR binding data provides excellent measures to prioritize X-ray experiments and consequently enable a better success rate in obtaining structural information. Information on the chemical structures of fragments binding to a protein can be used to perform similarity searches in compound libraries in order to establish structure-activity relationships as well as to explore particular scaffolds. At Roche we have applied this workflow for a number of targets and the experiences will be outlined in this review.

Computer-assisted analysis of spontaneous speech: quantification of basic parameters in aphasic and unimpaired language.

Although generally accepted as an important part of aphasia assessment, detailed analysis of spontaneous speech is rarely carried out in clinical practice mostly due to time limitations. The Aachener Sprachanalyse (ASPA; Aachen Speech Analysis) is a computer-assisted method for the quantitative analysis of German spontaneous speech that allows for a detailed assessment by means of linguistic basic parameters in an acceptable amount of time. It has previously been proven sensitive for monitoring changes over time. In this study, we present data of 52 aphasic participants whose spontaneous speech was analyzed retrospectively before and after an intensive therapy program. The measured changes are evaluated with reference to normative data of 60 non-brain-damaged speakers. Results confirm good sensitivity to document changes over time. Clinical relevance of changes is assessed with reference to critical score ranges derived from the normative data. Findings provide further evidence of the clinical applicability and usefulness of ASPA.

The prevalence of apraxia of speech in chronic aphasia after stroke: A bayesian hierarchical analysis.

Apraxia of speech is a motor speech disorder that occurs after lesions to the left cerebral hemisphere, most often concomitant with aphasia. It requires specific approaches in the study of its physiological and neuroanatomical basis and special expertise in clinical care. Knowing its prevalence in patients with aphasia after stroke is therefore relevant for planning specific resources in clinical research and in health care provision. Systematic studies of the frequency of this condition are lacking. We examined the frequency of apraxia of speech in a representative sample of 156 patients with chronic post-stroke aphasia. Three experts classified the patients' speech by best-practice auditory-perceptual methods. Bayesian hierarchical models were fitted to obtain probability distributions for prevalence estimates. A prior distribution was calculated in two steps, including Bayesian models for published frequency data (step 1) and prevalence estimates from experienced clinicians (step 2). Separate models were fitted for different severity ranges. Overall, a prevalence rate of .44 [.30, .58] was obtained. When only moderate and severe cases were taken into account, the rate was .35 [.23, .49]. After a further restriction to only severe impairment, prevalence dropped to .22 [.12, .34]. Patients identified with apraxia of speech had suffered more severe strokes according to clinical criteria and had more severe aphasias. The presence of apraxia of speech was predicted by the articulation/prosody and syntax rating scales of the Aachen Aphasia Test. Lower prevalence estimates published earlier are probably biased by low sensitivity of assessment instruments for mild speech impairment.

How different types of conceptual relations modulate brain activation during semantic priming.

Semantic priming, a well-established technique to study conceptual representation, has thus far produced variable fMRI results, both regarding the type of priming effects and their correlation with brain activation. The aims of the current study were (a) to investigate two types of semantic relations--categorical versus associative--under controlled processing conditions and (b) to investigate whether categorical and associative relations between words are correlated with response enhancement or response suppression. We used fMRI to examine neural correlates of semantic priming as subjects performed a lexical decision task with a long SOA (800 msec). Four experimental conditions were compared: categorically related trials (couch-bed), associatively related trials (couch-pillow), unrelated trials (couch-bridge), and nonword trials (couch-sibor). We found similar behavioral priming effects for both categorically and associatively related pairs. However, the neural priming effects differed: Categorically related pairs resulted in a neural suppression effect in the right MFG, whereas associatively related pairs resulted in response enhancement in the left IFG. A direct contrast between them revealed activation for categorically related trials in the right insular lobe. We conclude that perceptual and functional similarity of categorically related words may lead to response suppression within right-lateralized frontal regions that represent more retrieval effort and the recruitment of a broader semantic field. Associatively related pairs that require a different processing of the related target compared to the prime may lead to the response enhancement within left inferior frontal regions. Nevertheless, the differences between associative and categorical relations might be parametrical rather than absolutely distinct as both relationships recruit similar regions to a different degree.

Word frequency effects in the left IFG in dyslexic and normally reading children during picture naming and reading.

Word frequency effects have been reported in numerous neuroimaging studies with typically reading adults, emphasising the role of the left inferior frontal gyrus (LIFG). Within LIFG, different cytoarchitectonic modules (areas 44 and 45) have been related to phonological vs. lexico-semantic processing, respectively. This fMRI study investigated the differential impact of word frequency on LIFG activation in reading and picture naming in primary school children with and without developmental dyslexia. All children showed the typical LIFG frequency effect in both tasks. The effect was comparable in a fronto-orbital region anterior-inferior adjacent to area 45. During reading but not picture naming, a second effect was observed in area 44. Here, the fMRI effect for lexical frequency was stronger for the dyslexic than the normal readers. These findings demonstrate the neural underpinnings of a selective deficit in dyslexic children in the graphemic input lexicon, whereas abstract lexical representations appear to be processed equally well in dyslexic and normally reading children. To conclude, the present fMRI study demonstrated differential impact of word frequency on LIFG activation in primary school children during reading but not picture naming. Apart from extending previous knowledge from studies with adults to childhood, the study sheds further light on a potential neural mechanism for deficient grapheme-to-phoneme conversion in dyslexic children.

Ventral and dorsal pathways for language.

Built on an analogy between the visual and auditory systems, the following dual stream model for language processing was suggested recently: a dorsal stream is involved in mapping sound to articulation, and a ventral stream in mapping sound to meaning. The goal of the study presented here was to test the neuroanatomical basis of this model. Combining functional magnetic resonance imaging (fMRI) with a novel diffusion tensor imaging (DTI)-based tractography method we were able to identify the most probable anatomical pathways connecting brain regions activated during two prototypical language tasks. Sublexical repetition of speech is subserved by a dorsal pathway, connecting the superior temporal lobe and premotor cortices in the frontal lobe via the arcuate and superior longitudinal fascicle. In contrast, higher-level language comprehension is mediated by a ventral pathway connecting the middle temporal lobe and the ventrolateral prefrontal cortex via the extreme capsule. Thus, according to our findings, the function of the dorsal route, traditionally considered to be the major language pathway, is mainly restricted to sensory-motor mapping of sound to articulation, whereas linguistic processing of sound to meaning requires temporofrontal interaction transmitted via the ventral route.