Dissecting the multiple features of motor-speech problems in a genetic disorder

Project title: Dissecting the multiple features of motor-speech problems in a genetic disorder using structural and functional methods of brain imaging

Primary Supervisor: Professor Frederique Liegeois

Subsidiary Supervisor: Professor Faraneh Vargha-Khadem

Hypothesis:
It is predicted that affected KE members, who have problems with planning and execution of speech (1), and show both structural and functional abnormalities in motor-related structures (2-4), will also show impairments in (i) phonemic perception, (ii) implicit articulatory learning and (iii) temporal sequencing.

Aims and methods:
We have previously reported on an inherited neurodevelopmental disorder that selectively interferes with articulate speech, and with language function (1). Studies of the three-generational KE family, half of whose 30 members have a severe disorder of speech and language, highlighted the importance of the neostriatal system in the development of fine oromotor skills required for articulate speech, and language learning. We identified the core deficit in the affected KE members as one involving sequential articulation and orofacial praxis (5), viz a form of implicit, procedural motor learning disorder. The identification of the phenotype ultimately led to the discovery of FOXP2, the first gene implicated in the cascade of neurobiological processes that culminate in articulate speech and normal language function. Brain imaging studies of the KE members revealed structural and functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, namely, Broca's area, left premotor and motor cortices, and in parts of the neostriatal system (2-4). We now aim to dissect the phenotypic features of the FOXP2 mutation in the affected KE members, by searching for abnormalities in brain systems that subserve (i) phonological perception/processing, (ii) procedural/implicit learning of novel oromotor sequences, and (iii) timing and execution of these sequences (1):

Categorical perception - Given the link between perception and production (e.g. 6), we aim to investigate whether affected KE members, also show an impairment in phonemic perception. This question will be investigated by comparing behavioural standards of categorical perception in the affected KE members relative to unaffected members, and matched controls. In a functional MRI adaptation of the same paradigm, the neural substrate underlying categorical perception processes will be examined in the affected KE members and normal controls.
Implicit articulatory learning - Learning to articulate combinations of speech sounds that form new words from auditory exposures is crucial for the human capacity to produce fluent speech. To date, the procedural/implicit learning ability of the affected KE members has not been documented. We plan to examine this skill which accommodates new learning (7), in an fMRI experiment. Healthy controls and affected KE members will be repeatedly exposed to auditory nonwords, and they will be asked to repeat the nonwords. The aim is to determine how the affected members learn new articulatory sequences, and whether they recruit the same neural network as non-affected controls.
Temporal sequencing - Analysis and production of auditory temporal sequences (or sequencing), relies on the brain circuitry for complex vocal learning inasmuch as it involves special links between the auditory and motor systems. Previous reports suggest that a general deficit in sequencing might be associated with the speech production difficulties of the affected KE members (8). Sequencing abilities and their neural correlates will be studied by presenting members of the KE family with rhythmic patterns for recognition and reproduction. Using fMRI, the neural correlates underlying sequencing will be compared in individuals with and without a FOXP2 mutation.
Longitudinal evaluation - Now that the affected KE members have reached adulthood, their speech and language profiles will be re-assessed and compared with those obtained when they were children to determine the extent of compensation that may have resulted with increased language experience. These longitudinal studies will also assess the integrity of brain pathways in the speech and language network over time. The availability of a new 3T MRI along with the development of new brain imaging techniques providing quantitative measures of white matter integrity (Diffusion Tensor Imaging), tract delineation (tractography), and patterns of connectivity will enable the charting of auditory-motor interactions necessary for fluent speech production.

References:
1. Vargha-Khadem et al. (2005) FOXP2 and the neuroanatomy of speech and language. Nat Rev Neurosci.
2. Liegeois et al. (2003) Language fMRI abnormalities associated with FOXP2 gene
mutation. Nat Neurosci.
3. Watkins et al. (2002) MRI analysis of an inherited speech and language
disorder: structural brain abnormalities. Brain.
4. Liegeois et al. (2011) Endophenotypes of FOXP2: dysfunction within the human articulatory network. Eur J Paediatr Neurol.
5. Watkins et al. (2002) Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. Brain.
6. Yuen et al. (2010) Activation of articulatory information in speech perception. PNAS.
7. Rauschecker et al. (2008) Changes in neural activity associated with learning to articulate novel auditory pseudowords by covert repetition. Hum Brain Mapp.
8. Alcock et al. (2000) Pitch and timing abilities in inherited speech and language impairment. Brain Lang.