In-depth characterisation of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2.

BACKGROUND: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder: childhood apraxia of speech (CAS), and yet few cases have been reported, limiting knowledge of the condition. METHODS: Here we phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants (12 loss-of-function, five missense variants; 14 males; aged 2 to 62 years). Health and development (cognitive, motor, social domains) were examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. RESULTS: Speech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/26, 38%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (10/24, 42%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition. CONCLUSIONS: Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared with other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entry point for examining the neurobiological bases of speech disorder.

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.

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.

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.

Taboo: a novel paradigm to elicit aphasia-like trouble-indicating behaviour in normally speaking individuals.

Two important research lines in neuro- and psycholinguistics are studying natural or experimentally induced slips of the tongue and investigating the symptom patterns of aphasic individuals. Only few studies have focused on explaining aphasic symptoms by provoking aphasic symptoms in healthy speakers. While all experimental techniques have so far dealt with the single word or the sentence level, the current study intended to provoke aphasia-like trouble-indicating behaviour (i.e. prepairs and repairs) in the spontaneous language production of unimpaired speakers. In their descriptions of complex pictures, the participants were requested to avoid particular words terming central elements of the pictures. The results show that the error pattern provoked by the novel "taboo" paradigm resembled substantially the pattern of aphasic individuals. Consequently, the paradigm is applicable for further studies, e.g. for bringing forward the understanding of spontaneous language production or for comparing the neurofunctional basis of errors in healthy and aphasic speakers.

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.

Interaction of phonological awareness and 'magnocellular' processing during normal and dyslexic reading: behavioural and fMRI investigations.

We investigated whether phonological deficits are a consequence of magnocellular processing deficits in dyslexic and control children. In Experiment 1, children were tested for reading ability, phonological awareness, visuo-magnocellular motion perception, and attention shifting (sometimes considered as magnocellular function). A two-step cluster analysis of the behavioural scores revealed four clusters of children. Phonological awareness was correlated with attention (cluster musical sharp1) or motion detection (cluster musical sharp2), whereas attention and motion detection were correlated in cluster musical sharp3. In cluster musical sharp4, all variables were uncorrelated. In Experiment 2, the same variables plus auditory discrimination were tested with fMRI in a sub-sample of Experiment 1. Although dyslexics had reduced activation in visual or auditory cortex during motion detection or auditory discrimination, respectively, they had increased right frontal activation in areas 44 and 45 in all 'magnocellular' (including auditory) tasks. In contrasts, during phonological decisions, there was higher activation for good readers than dyslexics in left areas 44 and 45. Together, the two experiments give insight into the interplay of phonological and magnocellular processing during reading. Distinct left versus right frontal effects reveal partly different underlying neural mechanisms. These data contradict the view that phonological processing deficits in dyslexia necessarily result from impaired magnocellular functioning.

Cognitive levels of performance account for hemispheric lateralisation effects in dyslexic and normally reading children.

Recent theories of developmental dyslexia explain reading deficits in terms of deficient phonological awareness, attention, visual and auditory processing, or automaticity. Since dyslexia has a neurobiological basis, the question arises how the reader's proficiency in these cognitive variables affects the brain regions involved in visual word recognition. This question was addressed in two fMRI experiments with 19 normally reading children (Experiment 1) and 19 children with dyslexia (Experiment 2). First, reading-specific brain activation was assessed by contrasting the BOLD signal for reading aloud words vs. overtly naming pictures of real objects. Next, ANCOVAs with brain activation during reading the individuals' scores for all five cognitive variables assessed outside the scanner as covariates were performed. Whereas the normal readers' brain activation during reading showed co-variation effects predominantly in the right hemisphere, the reverse pattern was observed for the dyslexics. In particular, middle frontal gyrus, inferior parietal cortex, and precuneus showed contralateral effects for controls as compared to dyslexics. In line with earlier findings in the literature, these data hint at a global change in hemispheric asymmetry during cognitive processing in dyslexic readers, which, in turn, might affect reading proficiency.