Dissecting the neural circuits of FOXP2-dependent motor-speech deficits in the affected members of the KEO family using tractography and functional brain imaging

Supervisors: Professor Faraneh Vargha-Khadem and Dr Katrin Schulze

Aims: This project concerns new structural/functional brain imaging and neuropsychological studies of the affected members of the KE family who have a mutation in the FOXP2 gene. We aim to identify structural and functional brain abnormalities subserving (i) phonological perception/processing, (ii) procedural/implicit learning of novel oromotor sequences, and (iii) timing and execution of these sequences.

Background: The FOXP2 gene associated with the development of articulate speech and language ability was discovered in 2001 through studies of the affected members of the KE family who have a mutation in this gene which results unintelligible speech (1). We identified the core deficit in the affected KE members as one involving sequential articulation and orofacial praxis, viz a form of implicit, procedural motor learning disorder. Brain imaging studies of the KE members revealed structural and functional abnormalities in both cortical and subcortical motor-related areas. We now propose to address the following questions that elucidate the brain basis of the phenotype of this FOXP2-dependent motor speech disorder.

(i) Categorical perception (phonological perception/processing): Evidence is accumulating that motor-related brain structures known to be involved during speech production are also involved during speech perception, suggesting that speech perception and speech production share certain neural mechanisms. Our prediction is that affected KE members, who have problems with planning and execution of speech, will also show an impairment in phonemic perception. This question will be investigated through a behavioural study of categorical perception to determine the boundaries of phonetic categories, and through a functional MRI adaptation of the same paradigm to identify the neural substrate underlying categorical perception processes.
(ii) Learning of articulatory sequences (procedural/implicit learning): In humans, through its interaction with the frontal cortex, the neostriatum appears to play a role in rule learning of all kinds, including the type of motor sequence learning involved in articulation and speech. Structures that have been shown to be involved in vocal learning are mainly located in the left hemisphere and include the premotor cortex, supplementary motor area, inferior frontal gyrus, superior temporal cortex, and the cerebellum. Given the abnormal development of the fronto-neostriatal circuit in the affected KE members, we now propose to assess with fMRI how the affected members learn new articulatory sequences and which neural circuitry they utilise for procedural/implicit learning. We will evaluate (a) a potential learning effect by measuring the time participants need to repeat nonwords, (b) how well participants are able to pronounce the “learned” nonwords after the experiment, and (c) whether the neural correlates underlying the acquisition of new articulatory patterns differ between affected KE members and non-affected controls.
(iii) Analysis of temporal sequences and their timing: Analysis and production of auditory temporal sequences relies on the brain circuitry for complex vocal learning. Moreover, the neural substrates of vocal learning and sequencing appear to overlap in the brain (e.g., the basal ganglia and the supplementary motor areas). We will investigate the sequencing capacity of affected and unaffected KE members by presenting them with rhythmic patterns for them to compare (recognition task) or manually reproduce. Using fMRI, the neural correlates underlying sequencing can be compared in those with and without a FOXP2 mutation. Results will highlight the influence of timing and sequencing capacity on speech production, and may reveal a non-verbal processing and production deficit associated with the speech production problems of the affected KE members.

The relevance of the proposed project to the interface between basic and clinical science:
Studies of the FOXP2 gene and the KE family have provided one of the best examples of the two way interaction between clinical and basic science, starting from the phenotype of motor speech disorder to brain structure and function, and ultimately to gene expression and gene identification. The proposed experiments will again start at the phenotypic level to trace the anatomical basis and the connectivity patterns implicated in a discrete movement disorder that shares clinical features with other genetically-based motor related conditions.

References:
1) Vargha-Khadem F, Gadian DG, Copp A, & Mishkin M (2005) FOXP2 and the neuroanatomy of speech and language. Nat Rev Neurosci 6(2):131-138.
2) Liegeois F, Morgan AT, Connelly A, & Vargha-Khadem F (2011) Endophenotypes of FOXP2: dysfunction within the human articulatory network. Eur J Paediatr Neurol 15(4):283-288.
3) Pulvermuller F, et al. (2006) Motor cortex maps articulatory features of speech sounds. Proc Natl Acad Sci U S A 103(20):7865-7870.
4) Rauschecker AM, Pringle A, & Watkins KE (2008) Changes in neural activity associated with learning to articulate novel auditory pseudowords by covert repetition. Hum Brain Mapp 29(11):1231-1242.
5) Grahn JA & Rowe JB (2009) Feeling the beat: premotor and striatal interactions in musicians and nonmusicians during beat perception. The Journal of neuroscience : the official journal of the Society for Neuroscience 29(23):7540-7548 .