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.

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.

5-year course of therapy-induced recovery in chronic non-fluent aphasia - Three single cases.

Over a period of five years, three severely impaired chronic non-fluent aphasia patients with concomitant apraxia of speech (AOS) received annual treatment periods of specific rhythmic-melodic voice training SIPARI. This therapy concept focusses on improving planning, programming, and sequencing of speech movements emphasizing specifically the training of cognitive capabilities such as executive functions. Behavioral and neural data were assessed at the start of the therapy and continuously after each treatment period. As previously reported, a first major finding was that after the first treatment period, significant improvements in language and speech motor performance were measured going hand in hand with significant additional peri-lesional activation in all patients particularly in the posterior part of the left superior temporal gyrus. This activation pattern was continuously confirmed by each subsequent scan. However, assessments after the third treatment period yielded additional significant activations in dorsolateral prefrontal cortex regions, namely in the left middle and superior frontal gyri, and anterior cingulate gyrus resulting in a further statistically significant increase in speech profile level, an overall and clinically relevant measure of the severity of aphasia. On the basis of our results, we assume that even in long-term rehabilitation of severely impaired non-fluent aphasia patients the applied treatment may support coactivation with dorsolateral prefrontal regions, suggested to be particularly involved in cognitive processing. This left-lateralized dorsolateral prefrontal-parietal network is supposed to be engaged in domain-general aspects of active phonological memory. To the best of our knowledge, no comparable studies are available as yet. Therefore, we hope that our study may serve to attract more attention for the late stages of long-term rehabilitation, not at least as a challenge for therapists and researchers alike.

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.

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.

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.

Determinants of Concurrent Motor and Language Recovery during Intensive Therapy in Chronic Stroke Patients: Four Single-Case Studies.

Despite intensive research on mechanisms of recovery of function after stroke, surprisingly little is known about determinants of concurrent recovery of language and motor functions in single patients. The alternative hypotheses are that the two functions might either "fight for resources" or use the same mechanisms in the recovery process. Here, we present follow-up data of four exemplary patients with different base levels of motor and language abilities. We assessed functional scales and performed exact lesion analysis to examine the connection between lesion parameters and recovery potential in each domain. Results confirm that preservation of the corticospinal tracts (CSTs) is a neural predictor for good motor recovery while preservation of the arcuate fasciculus (AF) is important for a good language recovery. However, results further indicate that even patients with large lesions in CST, AF, and superior longitudinal fasciculus, respectively, are able to recover their motor/language abilities during intensive therapy. We further found some indicators of a facilitating interaction between motor and language recovery. Patients with positive improvement of motor skills after therapy also improved in language skills, while the patients with no motor improvements were not able to gain any language recovery.

What letters can "learn" from Arabic digits--fMRI-controlled single case therapy study of peripheral agraphia.

Research on (hand-)writing has revealed that Exner's area subserves transferring linguistic impulses into writing programmes. We report on a patient with a lesion affecting Broca's and Exner's area suffering from severe peripheral agraphia for letters but not for Arabic digits. Analogous to semantic (magnitude) information in numbers, we developed a specifically tailored writing training: additional mental imagery based semantic information was attached to letters. The training resulted in significant improvements. Imaging data revealed stronger fronto-parietal network activity including perilesional activation around Exner's area and precuneus for writing letters to dictation than for writing letters corresponding to their mental image expressions. Follow-up testing showed not only stable training effects but also an activation shift into the left angular gyrus. Results document neuronal correlates of a successful intervention by attaching additional meanings to letters in order to retrieve their grapho-motor patterns. These findings contribute to understanding the impact of Exner's area.

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.

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).

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.

The processing of lexical ambiguity in healthy ageing and Parkinson׳s disease: role of cortico-subcortical networks.

Previous neuroimaging studies showed that correct resolution of lexical ambiguity relies on the integrity of prefrontal and inferior parietal cortices. Whereas prefrontal brain areas were associated with executive control over semantic selection, inferior parietal areas were linked with access to modality-independent representations of semantic memory. Yet insufficiently understood is the contribution of subcortical structures in ambiguity processing. Patients with disturbed basal ganglia function such as Parkinson׳s disease (PD) showed development of discourse comprehension deficits evoked by lexical ambiguity. To further investigate the engagement of cortico-subcortical networks functional Magnetic Resonance Imaging (fMRI) was monitored during ambiguity resolution in eight early PD patients without dementia and 14 age- and education-matched controls. Participants were required to relate meanings to a lexically ambiguous target (homonym). Each stimulus consisted of two words arranged on top of a screen, which had to be attributed to a homonym at the bottom. Brain activity was found in bilateral inferior parietal (BA 39), right middle temporal (BA 21/22), left middle frontal (BA 10) and bilateral inferior frontal areas (BA 45/46). Extent and amplitude of activity in the angular gyrus changed depending on semantic association strength that varied between conditions. Less activity in the left caudate was associated with semantic integration deficits in PD. The results of the present study suggest a relationship between subtle language deficits and early stages of basal ganglia dysfunction. Uncovering impairments in ambiguity resolution may be of future use in the neuropsychological assessment of non-motor deficits in PD.

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.

The direction of word stress processing in German: evidence from a working memory paradigm.

There are contradicting assumptions and findings on the direction of word stress processing in German. To resolve this question, we asked participants to read tri-syllabic non-words and stress ambiguous words aloud. Additionally, they also performed a working memory (WM) task (2-back task). In non-word reading, participants' individual WM capacity was positively correlated with assignment of main stress to the antepenultimate syllable, which is most distant to the word's right edge, while a (complementary) negative correlation was observed with assignment of stress to the ultimate syllable. There was no significant correlation between WM capacity and stress assignment to the penultimate syllable, which has been claimed to be the default stress pattern in German. In reading stress ambiguous words, a similar but non-significant pattern was observed as in non-word reading. In sum, our results provide first psycholinguistic evidence supporting leftward stress processing in German. Our results do not lend support to the assumption of penultimate default stress in German. A specification of the lemma model is proposed which seems able to reconcile our findings and apparently contradicting assumptions and evidence.

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.

The neural correlates of agrammatism: Evidence from aphasic and healthy speakers performing an overt picture description task.

Functional brain imaging studies have improved our knowledge of the neural localization of language functions and the functional reorganization after a lesion. However, the neural correlates of agrammatic symptoms in aphasia remain largely unknown. The present fMRI study examined the neural correlates of morpho-syntactic encoding and agrammatic errors in continuous language production by combining three approaches. First, the neural mechanisms underlying natural morpho-syntactic processing in a picture description task were analyzed in 15 healthy speakers. Second, agrammatic-like speech behavior was induced in the same group of healthy speakers to study the underlying functional processes by limiting the utterance length. In a third approach, five agrammatic participants performed the picture description task to gain insights in the neural correlates of agrammatism and the functional reorganization of language processing after stroke. In all approaches, utterances were analyzed for syntactic completeness, complexity, and morphology. Event-related data analysis was conducted by defining every clause-like unit (CLU) as an event with its onset-time and duration. Agrammatic and correct CLUs were contrasted. Due to the small sample size as well as heterogeneous lesion sizes and sites with lesion foci in the insula lobe, inferior frontal, superior temporal and inferior parietal areas the activation patterns in the agrammatic speakers were analyzed on a single subject level. In the group of healthy speakers, posterior temporal and inferior parietal areas were associated with greater morpho-syntactic demands in complete and complex CLUs. The intentional manipulation of morpho-syntactic structures and the omission of function words were associated with additional inferior frontal activation. Overall, the results revealed that the investigation of the neural correlates of agrammatic language production can be reasonably conducted with an overt language production paradigm.

Neural underpinnings for model-oriented therapy of aphasic word production.

Model-oriented therapies of aphasic word production have been shown to be effective, with item-specific therapy effects being larger than generalisation effects for untrained items. However, it remains unclear whether semantic versus phonological therapy lead to differential effects, depending on type of lexical impairment. Functional imaging studies revealed that mainly left-hemisphere, perisylvian brain areas were involved in successful therapy-induced recovery of aphasic word production. However, the neural underpinnings for model-oriented therapy effects have not received much attention yet. We aimed at identifying brain areas indicating (1) general therapy effects using a naming task measured by functional magnetic resonance imaging (fMRI) in 14 patients before and after a 4-week naming therapy, which comprised increasing semantic and phonological cueing-hierarchies. We also intended to reveal differential effects (2) of training versus generalisation, (3) of therapy methods, and (4) of type of impairment as assessed by the connectionist Dell model. Training effects were stronger than generalisation effects, even though both were significant. Furthermore, significant impairment-specific therapy effects were observed for patients with phonological disorders (P-patients). (1) Left inferior frontal gyrus, pars opercularis (IFGoper), was a positive predictor of therapy gains while the right caudate was a negative predictor. Moreover, less activation decrease due to therapy in left-hemisphere temporo-parietal language areas was positively correlated with therapy gains. (2) Naming of trained compared to untrained words yielded less activation decrease in left superior temporal gyrus (STG) and precuneus, bilateral thalamus, and right caudate due to therapy. (3) Differential therapy effects could be detected in the right superior parietal lobule for the semantic method, and in regions involving bilateral anterior and mid cingulate, right precuneus, and left middle/superior frontal gyrus for the phonological method. (4) Impairment-specific changes of activation were found for P-patients in left IFGoper. Patients with semantic disorders (S-patients) relied on right frontal areas involving IFG, pars triangularis. After therapy, they revealed less activation decrease in areas involving left STG, caudate, paracentral lobule, and right rolandic operculum. Regarding naming performance, the present study corroborates previous findings on training and generalisation effects and reveals differential therapy effects for P-patients. Moreover, brain imaging results confirm a predominance of (1) general effects in the left brain hemisphere. (2) Brain regions related to visual strategy, monitoring/feedback, and articulatory patterns were characteristic for the familiar trained items. (3) Distinct regions associated with strategies, monitoring capacities, and linguistic information indicate the specific therapeutic influence on word retrieval. (4) While P-patients relied more on preserved phonological functions in the left hemisphere, S-patients revealed right-sided compensation of semantic processing as well as increased strategic efforts in both hemispheres.

Longitudinal changes in brains of patients with fluent primary progressive aphasia.

Primary progressive aphasia (PPA) is a rare clinical dementia syndrome with predominant, progressive language impairment. Clinical symptoms, linguistic impairment and the course of the disease may vary considerably between patients. In order to capture these aspects, longitudinal assessments of neurofunctional changes in PPA including their relationship to behaviour and clinical symptoms are mandatory, ideally at intervals shorter than 1 year. Here, we report a longitudinal fMRI study investigating the development of lexical processing and their neural basis in PPA patients over 1year. Four logopenic PPA patients and four matched controls were scanned 3 times (T1, T2, T3, at 6months intervals) while performing a visual lexical decision task on German words and pseudowords. Group differences for the lexicality effect (pseudowords>words) were assessed at time point T1 and its longitudinal changes in the BOLD signal associated with the lexicality effect were analysed. Brain atrophy was assessed with a high-resolution MPRAGE sequence and analysed using deformation based morphometry (DBM). From the very beginning of the study, PPA patients showed reduced left-hemispheric and increased right-hemispheric activations compared to controls. During the progression of the disease, activation increased predominantly in left posterior middle temporal gyrus (pMTG) and inferior frontal junction area, whereas the same regions decreased in activity in control brains. Interestingly, DBM data showed that this increase in activation in PPA patients was accompanied by progressing atrophy in the same regions. At a behavioural level, the accuracy in the lexical decision task was comparably high for both groups during the whole period of examination, despite some large variability between patients. To conclude, the dissociation between (i) maintained high performance, (ii) increased activity in regions involved in lexical access such as pMTG, and (iii) progressive atrophy of the very same regions supports the notion of a compensatory mechanism in brains of PPA patients for maintaining language while brain atrophy is progressing. The activity increase within a left-lateralised fronto-temporal network seems vital for high-level performance, whereas initial right-hemispheric recruitment of homologue language regions, which is reminiscent of that in vascular aphasics, has no continuous impact on lexical performance.

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.