Donepezil (DP), a cognitive-enhancing drug targeting the cholinergic system, combined with massed sentence repetition training augmented and speeded up recovery of speech production deficits in patients with chronic conduction aphasia and extensive left hemisphere infarctions (Berthier et al., 2014). Nevertheless, a still unsettled question is whether such improvements correlate with restorative structural changes in gray matter and white matter pathways mediating speech production. In the present study, we used pharmacological magnetic resonance imaging to study treatment-induced brain changes in gray matter and white matter tracts in a right-handed male with chronic conduction aphasia and a right subcortical lesion (crossed aphasia). A single-patient, open-label multiple-baseline design incorporating two different treatments and two post-treatment evaluations was used. The patient received an initial dose of DP (5 mg/day) which was maintained during 4 weeks and then titrated up to 10 mg/day and administered alone (without aphasia therapy) during 8 weeks (Endpoint 1). Thereafter, the drug was combined with an audiovisual repetition-imitation therapy (Look-Listen-Repeat, LLR) during 3 months (Endpoint 2). Language evaluations, diffusion weighted imaging (DWI), and voxel-based morphometry (VBM) were performed at baseline and at both endpoints in JAM and once in 21 healthy control males. Treatment with DP alone and combined with LLR therapy induced marked improvement in aphasia and communication deficits as well as in selected measures of connected speech production, and phrase repetition. The obtained gains in speech production remained well-above baseline scores even 4 months after ending combined therapy. Longitudinal DWI showed structural plasticity in the right frontal aslant tract and direct segment of the arcuate fasciculus with both interventions. VBM revealed no structural changes in other white matter tracts nor in cortical areas linked by these tracts. In conclusion, cholinergic potentiation alone and combined with a model-based aphasia therapy improved language deficits by promoting structural plastic changes in right white matter tracts.
Keywords: aphasia therapy; crossed aphasia; donepezil; neuroimaging; structural plasticity.