Neurofilaments and progranulin are related to atrophy in frontotemporal lobar degeneration - A transdiagnostic study cross-validating atrophy and fluid biomarkers.

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.

Maturation of consonant perception, but not vowel perception, predicts lexical skills at 12 months.

Consonants and vowels differentially contribute to lexical acquisition. From 8 months on, infants' preferential reliance on consonants has been shown to predict their lexical outcome. Here, the predictive value of German-learning infants' (n = 58, 29 girls, 29 boys) trajectories of consonant and vowel perception, indicated by the electrophysiological mismatch response, across 2, 6, and 10 months for later lexical acquisition was studied. The consonant-perception trajectory from 2 to 6 months (ß = -2.95) and 6 to 10 months (ß = -.91), but not the vowel-perception trajectory, significantly predicted receptive vocabulary at 12 months. These results reveal an earlier predictive value of consonant perception for word learning than previously found, and a particular role of the longitudinal maturation of this skill in lexical acquisition.

Web-based language production experiments: Semantic interference assessment is robust for spoken and typed response modalities.

For experimental research on language production, temporal precision and high quality of the recorded audio files are imperative. These requirements are a considerable challenge if language production is to be investigated online. However, online research has huge potential in terms of efficiency, ecological validity and diversity of study populations in psycholinguistic and related research, also beyond the current situation. Here, we supply confirmatory evidence that language production can be investigated online and that reaction time (RT) distributions and error rates are similar in written naming responses (using the keyboard) and typical overt spoken responses. To assess semantic interference effects in both modalities, we performed two pre-registered experiments (n = 30 each) in online settings using the participants' web browsers. A cumulative semantic interference (CSI) paradigm was employed that required naming several exemplars of semantic categories within a seemingly unrelated sequence of objects. RT is expected to increase linearly for each additional exemplar of a category. In Experiment 1, CSI effects in naming times described in lab-based studies were replicated. In Experiment 2, the responses were typed on participants' computer keyboards, and the first correct key press was used for RT analysis. This novel response assessment yielded a qualitatively similar, very robust CSI effect. Besides technical ease of application, collecting typewritten responses and automatic data preprocessing substantially reduce the work load for language production research. Results of both experiments open new perspectives for research on RT effects in language experiments across a wide range of contexts. JavaScript- and R-based implementations for data collection and processing are available for download.

BONEs not CATs attract DOGs: Semantic context effects for picture naming in the lesioned language network.

The breakdown of rapid and accurate retrieval of words is a hallmark of aphasic speech and a prime target of therapeutic intervention. Complementary, psycho- and neurolinguistic research have developed a spectrum of models, how and by which neuronal network uncompromised speakers can rely on remarkable lexical retrieval capacities. Motivated by both lines of research we invited 32 participants with a chronic left hemispheric brain lesion to name pictures in the presence of distractor words. This picture-word-interference (PWI) paradigm is widely used in psycho- and neurolinguistic research. We find that also after brain lesion categorically related words (CAT â†’ [dog]picture) impede naming, while associatively related words (BONE â†’ [dog]picture) ease access, when compared to unrelated distractor words. The effects largely affecting latencies in neurotypical populations, are reproduced for error rate in our participants with lesions in the language network. Unsurprisingly, overall naming abilities varied greatly across patients. Notably, however, the two effects (categorical interference / associative facilitation) differ between participants. Correlating performance with lesion patterns we find support for the notion of a divergence of brain areas affording different aspects of the task: (i) lesions in the left middle temporal gyurs (MTG) deteriorate overall naming, confirming previous work; more notably, (ii) lesions comprising the inferior frontal hub (inferior frontal gyrus, IFG) of the language-network increase the interference effect for the categorical condition; on the contrary, (iii) lesions to the mid-to-posterior temporal hub (posterior middle and superior temporal gyri, pMTG/ pSTG) increase the facilitatory effect for the associative condition on error rates. The findings can be accommodated in a neuro-linguistic framework, which localizes lexical activation but also lexical interference in posterior parts of the language network (pMTG/pITG); conversely, selection between co-activated categorically related entries is afforded by frontal language areas (IFG). While purely experimental in nature our study highlights that lesion site differentially influences specific aspects of word retrieval. Since confrontational naming is a cornerstone of aphasia rehabilitation, this may be of note when designing and evaluating novel therapeutic regimes.

Clinico-genetic findings in 509 frontotemporal dementia patients.

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.

Utility of the Repeat and Point Test for Subtyping Patients With Primary Progressive Aphasia.

BACKGROUND: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). OBJECTIVE: The aim was to examine the utility of the German version of the Repeat and Point (R&P) Test for subtyping patients with PPA. METHOD: During the R&P Test, the examiner reads out aloud a noun and the participants are asked to repeat the word and subsequently point to the corresponding picture. Data from 204 patients (68 svPPA, 85 nfvPPA, and 51 lvPPA) and 33 healthy controls were analyzed. RESULTS: Controls completed both tasks with >90% accuracy. Patients with svPPA had high scores in repetition (mean=9.2±1.32) but low scores in pointing (mean=6±2.52). In contrast, patients with nfvPPA and lvPPA performed comparably in both tasks with lower scores in repetition (mean=7.4±2.7 for nfvPPA and 8.2±2.34 for lvPPA) but higher scores in pointing (mean=8.9±1.41 for nfvPPA and 8.6±1.62 for lvPPA). The R&P Test had high accuracy discriminating svPPA from nfvPPA (83% accuracy) and lvPPA (79% accuracy). However, there was low accuracy discriminating nfvPPA from lvPPA (<60%). CONCLUSION: The R&P Test helps to differentiate svPPA from 2 nonsemantic variants (nfvPPA and lvPPA). However, additional tests are required for the differentiation of nfvPPA and lvPPA.

Semantic Interference through Multiple Distractors in Picture Naming in People with Aphasia.

When we refer to an object or concept by its name, activation of semantic and categorical information is necessary to retrieve the correct lexical representation. Whereas in neurotypical individuals it is well established that semantic context can interfere with or facilitate lexical retrieval, these effects are much less studied in people with lesions to the language network and impairment at different steps of lexical-semantic processing. Here, we applied a novel picture naming paradigm, where multiple categorically related and unrelated words were presented as distractors before a to-be-named target picture. Using eye tracking, we investigated preferential fixation on the cohort members versus nonmembers. Thereby, we can judge the impact of explicit acknowledgment of the category and its effect on semantic interference. We found that, in contrast to neurotypical participants [van Scherpenberg, C., Abdel Rahman, R., & Obrig, H. A novel multiword paradigm for investigating semantic context effects in language production. PLoS One, 15, e0230439, 2020], participants suffering from mild to moderate aphasia did not show a fixation preference on category members but still showed a large interference effect of ∼35 msec, confirming the implicit mechanism of categorical interference. However, preferential fixation on the categorically related cohort words correlated with clinical tests regarding nonverbal semantic abilities and integrity of the anterior temporal lobe. This highlights the role of supramodal semantics for explicit recognition of a semantic category, while semantic interference is triggered if the threshold of lexical cohort activation is reached. Confirming psycholinguistic evidence, the demonstration of a large and persistent interference effect through implicit lexico-semantic activation is important to understand deficits in people with a lesion in thelanguage network, potentially relevant for individualized intervention aiming at improving naming skills.

Recursive hierarchical embedding in vision is impaired by posterior middle temporal gyrus lesions.

The generation of hierarchical structures is central to language, music and complex action. Understanding this capacity and its potential impairments requires mapping its underlying cognitive processes to the respective neuronal underpinnings. In language, left inferior frontal gyrus and left posterior temporal cortex (superior temporal sulcus/middle temporal gyrus) are considered hubs for syntactic processing. However, it is unclear whether these regions support computations specific to language or more generally support analyses of hierarchical structure. Here, we address this issue by investigating hierarchical processing in a non-linguistic task. We test the ability to represent recursive hierarchical embedding in the visual domain by contrasting a recursion task with an iteration task. The recursion task requires participants to correctly identify continuations of a hierarchy generating procedure, while the iteration task applies a serial procedure that does not generate new hierarchical levels. In a lesion-based approach, we asked 44 patients with left hemispheric chronic brain lesion to perform recursion and iteration tasks. We modelled accuracies and response times with a drift diffusion model and for each participant obtained parametric estimates for the velocity of information accumulation (drift rates) and for the amount of information accumulated before a decision (boundary separation). We then used these estimates in lesion-behaviour analyses to investigate how brain lesions affect specific aspects of recursive hierarchical embedding. We found that lesions in the posterior temporal cortex decreased drift rate in recursive hierarchical embedding, suggesting an impaired process of rule extraction from recursive structures. Moreover, lesions in inferior temporal gyrus decreased boundary separation. The latter finding does not survive conservative correction but suggests a shift in the decision criterion. As patients also participated in a grammar comprehension experiment, we performed explorative correlation-analyses and found that visual and linguistic recursive hierarchical embedding accuracies are correlated when the latter is instantiated as sentences with two nested embedding levels. While the roles of the inferior temporal gyrus and posterior temporal cortex in linguistic processes are well established, here we show that posterior temporal cortex lesions slow information accumulation (drift rate) in the visual domain. This suggests that posterior temporal cortex is essential to acquire the (knowledge) representations necessary to parse recursive hierarchical embedding in visual structures, a finding mimicking language acquisition in young children. On the contrary, inferior frontal gyrus lesions seem to affect recursive hierarchical embedding processing by interfering with more general cognitive control (boundary separation). This interesting separation of roles, rooted on a domain-general taxonomy, raises the question of whether such cognitive framing is also applicable to other domains.

The effect of high vs. low intensity neuropsychological treatment on working memory in patients with acquired brain injury.

AIM: To evaluate the combined effect of compensation therapy and functional training on working memory (WM) in patients with acquired injury and chronic cognitive deficits by investigating the dose-response relationship and specificity of transfer effects. RESEARCH DESIGN: Double-blind randomized controlled trial. METHODS: All patients underwent 4 weeks of compensation therapy in a day-care setting. In addition, they received either 20 sessions of computer-based WM training (n = 11) or attention training (n = 9). Transfer effects on cognition and their functional relevance in daily life were assessed before treatment, after 2 weeks (10 additional training sessions), and after 4 weeks (20 additional training sessions) of therapy. RESULTS: The combined treatment led to significant improvements in WM performance, verbal memory, and self-reported changes in daily life. The amount of training was identified to modulate efficacy: Significant improvements showed only in the later training phase. We observed no differences between the two training schemes (WM vs. attentional training). CONCLUSIONS: Even in the chronic phase after brain lesion WM performance can be enhanced by the combination of compensation therapy and computerized cognitive training when applied intensely; both a more general attention and a specific WM training regimen are effective.

Obligatory and facultative brain regions for voice-identity recognition.

Recognizing the identity of others by their voice is an important skill for social interactions. To date, it remains controversial which parts of the brain are critical structures for this skill. Based on neuroimaging findings, standard models of person-identity recognition suggest that the right temporal lobe is the hub for voice-identity recognition. Neuropsychological case studies, however, reported selective deficits of voice-identity recognition in patients predominantly with right inferior parietal lobe lesions. Here, our aim was to work towards resolving the discrepancy between neuroimaging studies and neuropsychological case studies to find out which brain structures are critical for voice-identity recognition in humans. We performed a voxel-based lesion-behaviour mapping study in a cohort of patients (n = 58) with unilateral focal brain lesions. The study included a comprehensive behavioural test battery on voice-identity recognition of newly learned (voice-name, voice-face association learning) and familiar voices (famous voice recognition) as well as visual (face-identity recognition) and acoustic control tests (vocal-pitch and vocal-timbre discrimination). The study also comprised clinically established tests (neuropsychological assessment, audiometry) and high-resolution structural brain images. The three key findings were: (i) a strong association between voice-identity recognition performance and right posterior/mid temporal and right inferior parietal lobe lesions; (ii) a selective association between right posterior/mid temporal lobe lesions and voice-identity recognition performance when face-identity recognition performance was factored out; and (iii) an association of right inferior parietal lobe lesions with tasks requiring the association between voices and faces but not voices and names. The results imply that the right posterior/mid temporal lobe is an obligatory structure for voice-identity recognition, while the inferior parietal lobe is only a facultative component of voice-identity recognition in situations where additional face-identity processing is required.

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.

Universal and language-specific sublexical cues in speech perception: a novel electroencephalography-lesion approach.

SEE CAPPA DOI101093/BRAIN/AWW090 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE : The phonological structure of speech supports the highly automatic mapping of sound to meaning. While it is uncontroversial that phonotactic knowledge acts upon lexical access, it is unclear at what stage these combinatorial rules, governing phonological well-formedness in a given language, shape speech comprehension. Moreover few studies have investigated the neuronal network affording this important step in speech comprehension. Therefore we asked 70 participants-half of whom suffered from a chronic left hemispheric lesion-to listen to 252 different monosyllabic pseudowords. The material models universal preferences of phonotactic well-formedness by including naturally spoken pseudowords and digitally reversed exemplars. The latter partially violate phonological structure of all human speech and are rich in universally dispreferred phoneme sequences while preserving basic auditory parameters. Language-specific constraints were modelled in that half of the naturally spoken pseudowords complied with the phonotactics of the native language of the monolingual participants (German) while the other half did not. To ensure universal well-formedness and naturalness, the latter stimuli comply with Slovak phonotactics and all stimuli were produced by an early bilingual speaker. To maximally attenuate lexico-semantic influences, transparent pseudowords were avoided and participants had to detect immediate repetitions, a task orthogonal to the contrasts of interest. The results show that phonological 'well-formedness' modulates implicit processing of speech at different levels: universally dispreferred phonological structure elicits early, medium and late latency differences in the evoked potential. On the contrary, the language-specific phonotactic contrast selectively modulates a medium latency component of the event-related potentials around 400 ms. Using a novel event-related potential-lesion approach allowed us to furthermore supply first evidence that implicit processing of these different phonotactic levels relies on partially separable brain areas in the left hemisphere: contrasting forward to reversed speech the approach delineated an area comprising supramarginal and angular gyri. Conversely, the contrast between legal versus illegal phonotactics consistently projected to anterior and middle portions of the middle temporal and superior temporal gyri. Our data support the notion that phonological structure acts on different stages of phonologically and lexically driven steps of speech comprehension. In the context of previous work we propose context-dependent sensitivity to different levels of phonotactic well-formedness.

Dissociation of amyloid biomarkers in PET and CSF in Alzheimer's disease: a case report.

BACKGROUND: Recently, biomarkers have been suggested to be incorporated into diagnostic criteria for Alzheimer's disease (AD). Regarding disease-specific brain amyloid-beta deposition these comprise low amyloid-beta 1-42 in cerebrospinal fluid (CSF) and positive positron emission tomography (PET) amyloid imaging, while neuronal degeneration is evidenced by high total and phosphorylated tau levels in CSF (t-/p-tau), regional hypometabolism ([(18)F]fluorodeoxyglucose PET, FDG-PET) and characteristic atrophy-patterns (magnetic resonance imaging, MRI). CASE PRESENTATION: Here we present a case of clinically and biomarker supported AD (CSF t-/p-tau, MRI, FDG-PET) in a 59-year-old Caucasian man in whom indicators of amyloid-beta deposition dissociated between CSF parameters and the respective PET imaging. CONCLUSIONS: Such cases highlight the necessity to better understand potential dissociations between PET and CSF data for amyloid-beta biomarkers, because they are currently considered interchangeably valid with regard to in-vivo evidence for AD pathology. This is more important since amyloid deposition markers can be considered a very first prognostic indicator of imminent AD, prior to neurodegenerative biomarkers and cognitive symptoms. The case illustrates the need for further longitudinal data on potential dissociations of AD biomarkers to devise recommendations for their better prognostic and diagnostic interpretation in the future.

Lesion correlates of patholinguistic profiles in chronic aphasia: comparisons of syndrome-, modality- and symptom-level assessment.

One way to investigate the neuronal underpinnings of language competence is to correlate patholinguistic profiles of aphasic patients to corresponding lesion sites. Constituting the beginnings of aphasiology and neurolinguistics over a century ago, this approach has been revived and refined in the past decade by statistical approaches mapping continuous variables (providing metrics that are not simply categorical) on voxel-wise lesion information (voxel-based lesion-symptom mapping). Here we investigate whether and how voxel-based lesion-symptom mapping allows us to delineate specific lesion patterns for differentially fine-grained clinical classifications. The latter encompass 'classical' syndrome-based approaches (e.g. Broca's aphasia), more symptom-oriented descriptions (e.g. agrammatism) and further refinement to linguistic sub-functions (e.g. lexico-semantic deficits for inanimate versus animate items). From a large database of patients treated for aphasia of different aetiologies (n = 1167) a carefully selected group of 102 first ever ischaemic stroke patients with chronic aphasia (∅ 12 months) were included in a VLSM analysis. Specifically, we investigated how performance in the Aachen Aphasia Test-the standard clinical test battery for chronic aphasia in German-relates to distinct brain lesions. The Aachen Aphasia Test evaluates aphasia on different levels: a non-parametric discriminant procedure yields probabilities for the allocation to one of the four 'standard' syndromes (Broca, Wernicke, global and amnestic aphasia), whereas standardized subtests target linguistic modalities (e.g. repetition), or even more specific symptoms (e.g. phoneme repetition). Because some subtests of the Aachen Aphasia Test (e.g. for the linguistic level of lexico-semantics) rely on rather coarse and heterogeneous test items we complemented the analysis with a number of more detailed clinically used tests in selected mostly mildly affected subgroups of patients. Our results indicate that: (i) Aachen Aphasia Test-based syndrome allocation allows for an unexpectedly concise differentiation between 'Broca's' and 'Wernicke's' aphasia corresponding to non-overlapping anterior and posterior lesion sites; whereas (ii) analyses for modalities and specific symptoms yielded more circumscribed but partially overlapping lesion foci, often cutting across the above syndrome territories; and (iii) especially for lexico-semantic capacities more specialized clinical test-batteries are required to delineate precise lesion patterns at this linguistic level. In sum this is the first report on a successful lesion-delineation of syndrome-based aphasia classification highlighting the relevance of vascular distribution for the syndrome level while confirming and extending a number of more linguistically motivated differentiations, based on clinically used tests. We consider such a comprehensive view reaching from the syndrome to a fine-grained symptom-oriented assessment mandatory to converge neurolinguistic, patholinguistic and clinical-therapeutic knowledge on language-competence and impairment.

Facilitation of inferior frontal cortex by transcranial direct current stimulation induces perceptual learning of severely degraded speech.

Perceptual learning requires the generalization of categorical perceptual sensitivity from trained to untrained items. For degraded speech, perceptual learning modulates activation in a left-lateralized network, including inferior frontal gyrus (IFG) and inferior parietal cortex (IPC). Here we demonstrate that facilitatory anodal transcranial direct current stimulation (tDCS(anodal)) can induce perceptual learning in healthy humans. In a sham-controlled, parallel design study, 36 volunteers were allocated to the three following intervention groups: tDCS(anodal) over left IFG, IPC, or sham. Participants decided on the match between an acoustically degraded and an undegraded written word by forced same-different choice. Acoustic degradation varied in four noise-vocoding levels (2, 3, 4, and 6 bands). Participants were trained to discriminate between minimal (/Tisch/-FISCH) and identical word pairs (/Tisch/-TISCH) over a period of 3 d, and tDCS(anodal) was applied during the first 20 min of training. Perceptual sensitivity (d') for trained word pairs, and an equal number of untrained word pairs, was tested before and after training. Increases in d' indicate perceptual learning for untrained word pairs, and a combination of item-specific and perceptual learning for trained word pairs. Most notably for the lowest intelligibility level, perceptual learning occurred only when tDCS(anodal) was applied over left IFG. For trained pairs, improved d' was seen on all intelligibility levels regardless of tDCS intervention. Over left IPC, tDCS(anodal) did not modulate learning but instead introduced a response bias during training. Volunteers were more likely to respond "same," potentially indicating enhanced perceptual fusion of degraded auditory with undegraded written input. Our results supply first evidence that neural facilitation of higher-order language areas can induce perceptual learning of severely degraded speech.

NIRS in clinical neurology - a 'promising' tool?

Near-infrared spectroscopy (NIRS) has become a relevant research tool in neuroscience. In special populations such as infants and for special tasks such as walking, NIRS has asserted itself as a low resolution functional imaging technique which profits from its ease of application, portability and the option to co-register other neurophysiological and behavioral data in a 'near natural' environment. For clinical use in neurology this translates into the option to provide a bed-side oximeter for the brain, broadly available at comparatively low costs. However, while some potential for routine brain monitoring during cardiac and vascular surgery and in neonatology has been established, NIRS is largely unknown to clinical neurologists. The article discusses some of the reasons for this lack of use in clinical neurology. Research using NIRS in three major neurologic diseases (cerebrovascular disease, epilepsy and headache) is reviewed. Additionally the potential to exploit the established position of NIRS as a functional imaging tool with regard to clinical questions such as preoperative functional assessment and neurorehabilitation is discussed.

A wearable multi-channel fNIRS system for brain imaging in freely moving subjects.

Functional near infrared spectroscopy (fNIRS) is a versatile neuroimaging tool with an increasing acceptance in the neuroimaging community. While often lauded for its portability, most of the fNIRS setups employed in neuroscientific research still impose usage in a laboratory environment. We present a wearable, multi-channel fNIRS imaging system for functional brain imaging in unrestrained settings. The system operates without optical fiber bundles, using eight dual wavelength light emitting diodes and eight electro-optical sensors, which can be placed freely on the subject's head for direct illumination and detection. Its performance is tested on N=8 subjects in a motor execution paradigm performed under three different exercising conditions: (i) during outdoor bicycle riding, (ii) while pedaling on a stationary training bicycle, and (iii) sitting still on the training bicycle. Following left hand gripping, we observe a significant decrease in the deoxyhemoglobin concentration over the contralateral motor cortex in all three conditions. A significant task-related ΔHbO2 increase was seen for the non-pedaling condition. Although the gross movements involved in pedaling and steering a bike induced more motion artifacts than carrying out the same task while sitting still, we found no significant differences in the shape or amplitude of the HbR time courses for outdoor or indoor cycling and sitting still. We demonstrate the general feasibility of using wearable multi-channel NIRS during strenuous exercise in natural, unrestrained settings and discuss the origins and effects of data artifacts. We provide quantitative guidelines for taking condition-dependent signal quality into account to allow the comparison of data across various levels of physical exercise. To the best of our knowledge, this is the first demonstration of functional NIRS brain imaging during an outdoor activity in a real life situation in humans.

Functional near-infrared spectroscopy in pediatric clinical research: Different pathophysiologies and promising clinical applications.

Over its 30 years of existence, functional near-infrared spectroscopy (fNIRS) has matured into a highly versatile tool to study brain function in infants and young children. Its advantages, amongst others, include its ease of application and portability, the option to combine it with electrophysiology, and its relatively good tolerance to movement. As shown by the impressive body of fNIRS literature in the field of cognitive developmental neuroscience, the method's strengths become even more relevant for (very) young individuals who suffer from neurological, behavioral, and/or cognitive impairment. Although a number of studies have been conducted with a clinical perspective, fNIRS cannot yet be considered as a truly clinical tool. The first step has been taken in this direction by studies exploring options in populations with well-defined clinical profiles. To foster further progress, here, we review several of these clinical approaches to identify the challenges and perspectives of fNIRS in the field of developmental disorders. We first outline the contributions of fNIRS in selected areas of pediatric clinical research: epilepsy, communicative and language disorders, and attention-deficit/hyperactivity disorder. We provide a scoping review as a framework to allow the highlighting of specific and general challenges of using fNIRS in pediatric research. We also discuss potential solutions and perspectives on the broader use of fNIRS in the clinical setting. This may be of use to future research, targeting clinical applications of fNIRS in children and adolescents.

The role of left temporo-parietal and inferior frontal cortex in comprehending syntactically complex sentences: A brain stimulation study.

BACKGROUND AND OBJECTIVES: Syntactic competence relies on a left-lateralized network converging on hubs in inferior-frontal and posterior-temporal cortices. We address the question whether anodal transcranial direct current stimulation (a-tDCS) over these hubs can modulate comprehension of sentences, whose syntactic complexity systematically varied along the factors embedding depths and canonicity. Semantic content and length of the sentences were kept identical and forced choice picture matching was required after the full sentence had been presented. METHODS: We used a single-blind, within-subject, sham-controlled design, applying a-tDCS targeting left posterior tempo-parietal (TP) and left inferior frontal cortex (FC). Stimulation sites were determined by individual neuro-navigation. 20 participants were included of whom 19 entered the analysis. Results were analysed using (generalized) mixed models. In a pilot-experiment in another group of 20 participants we validated the manipulation of syntactic complexity by the two factors embedding depth and argument-order. RESULTS: Reaction times increased and accuracy decreased with higher embedding depth and non-canonical argument order in both experiments. Notably a-tDCS over TP enhanced sentence-to-picture matching, while FC-stimulation showed no consistent effect. Moreover, the analysis disclosed a session effect, indicating improvements of task performance especially regarding speed. CONCLUSIONS: We conclude that the posterior 'hub' of the neuronal network affording syntactic analysis represents a 'bottleneck', likely due to working-memory capacity and the challenges of mapping semantic to syntactic information allowing for role assignment. While this does not challenge the role of left inferior-frontal cortex for syntax processing and novel-grammar learning, the application of highly established syntactic rules during sentence comprehension may be considered optimized, thus not augmentable by a-tDCS in the uncompromised network. SIGNIFICANCE STATEMENT: Anodal transcranial direct current stimulation (a-tDCS) over left temporo-parietal cortex enhances comprehension of complex sentences in uncompromised young speakers. Since a-tDCS over left frontal cortex did not elicit any change, the 'bottleneck' for the understanding of complex sentences seems to be the posterior, temporo-parietal rather than the anterior inferior-frontal 'hub' of language processing. Regarding the attested role of inferior-frontal cortex in syntax processing, we suggest that its function is optimized in competent young speakers, preventing further enhancement by (facilitatory) tDCS. Results shed light on the functional anatomy of syntax processing during sentence comprehension; moreover, they open perspectives for research in the lesioned language network of people with syntactic deficits due to aphasia.

Electrophysiological correlates of basic semantic composition in people with aphasia.

The neuroanatomical correlates of basic semantic composition have been investigated in previous neuroimaging and lesion studies, but research on the electrophysiology of the involved processes is scarce. A large literature on sentence-level event-related potentials (ERPs) during semantic processing has identified at least two relevant components - the N400 and the P600. Other studies demonstrated that these components are reduced and/or delayed in people with aphasia (PWA). However, it remains to be shown if these findings generalize beyond the sentence level. Specifically, it is an open question if an alteration in ERP responses in PWA can also be observed during basic semantic composition, providing a potential future diagnostic tool. The present study aimed to elucidate the electrophysiological dynamics of basic semantic composition in a group of post-stroke PWA. We included 20 PWA and 20 age-matched controls (mean age 58 years) and measured ERP responses while they performed a plausibility judgment task on two-word phrases that were either meaningful ("anxious horse"), anomalous ("anxious wood") or had the noun replaced by a pseudoword ("anxious gufel"). The N400 effect for anomalous versus meaningful phrases was similar in both groups. In contrast, unlike the control group, PWA did not show an N400 effect between pseudoword and meaningful phrases. Moreover, both groups exhibited a parietal P600 effect towards pseudoword phrases, while PWA showed an additional P600 over frontal electrodes. Finally, PWA showed an inverse correlation between the magnitude of the N400 and P600 effects: PWA exhibiting no or even reversed N400 effects towards anomalous and pseudoword phrases showed a stronger P600 effect. These results may reflect a compensatory mechanism which allows PWA to arrive at the correct interpretation of the phrase. When compositional processing capacities are impaired in the early N400 time-window, PWA may make use of a more elaborate re-analysis process reflected in the P600.