Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Logopenic Variant PPA

Language deficits are a common feature of neurodegenerative disorders, and are the primary deficit in primary progressive aphasia (PPA), a syndrome accounting for approximately 2/3 fronto-temporal lobar dementia (FTLD) variants, and at least one Alzheimer's disease (AD) variant. Language deficits dramatically impair communication and quality of life for both patients and caregivers. PPA usually has an early onset (50-65 years of age), detrimentally affecting work and family life. There are no disease-modifying pharmacological agents for PPA and the only treatment available is a few sessions of compensatory speech-language therapy. In the first cycle of this award the investigators asked the question of whether language therapy effects could be augmented by electrical stimulation. The investigators conducted the largest to-date randomized, double-blind, sham-controlled, crossover, clinical trial to determine the effects of transcranial direct current stimulation (tDCS) in PPA. The investigators found that tDCS over the left inferior frontal gyrus (L_IFG), one of the major language hubs in the brain, significantly augments the effects of a written naming and spelling intervention. However, the investigators found great heterogeneity in the effects of tDCS. Surprisingly, patients with the largest tDCS effects in the therapy task and the largest generalization effects to other tasks were the non-fluent variant (nfvPPA) group, with an epicenter of atrophy in the L_IFG. Although the investigators showed that those who improved naming the most, after stimulation of subjects' L_IFG, were those who have atrophy there, a key question remains. What is the explanation: (1) the great plasticity of the L_IFG (as recently shown in post-stroke aphasia) or (2) a general principle of neuromodulation, i.e., stimulation is most effective over atrophied and compromised areas. The latter hypothesis is strengthened by the absence of correlation between atrophy and functional connectivity (FC), which was shown to be one of the mechanisms of tDCS effects, the other being changes in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

Therefore, to address the above question, the investigators will stimulate another major area of atrophy in PPA, the parietal cortex. The anterior inferior parietal cortex, and in particular the left supramarginal gyrus (L_SMG), specialize in phonological processing, namely phonological verbal short-term memory (vSTM), i.e., the ability to temporarily store phonological (and graphemic) information in order. The domain of vSTM affects many language tasks (repetition, naming, syntax), which makes it an ideal treatment target and the L_SMG an ideal stimulation target, since generalization of tDCS effects to other language tasks is driven by the function (computation) of the stimulated area. The proposed research capitalizes on the investigators' extensive experience with tDCS in PPA (18 published and 7 under review papers from the previous clinical trial) and will experimentally address the fundamental question of whether stimulation over atrophied and compromised cortex is most effective. By testing a fundamental principle of neuromodulation in a devastating neurodegenerative disorder, the investigators will significantly advance the field of neurorehabilitation in early-onset dementias.

Aim 1: To determine whether vSTM treatment ('RAM', for 'Repeat After Me') combined with high definition (HD)-tDCS over the L_SMG will be more effective for patients with the local epicenter of atrophy there than for patients with frontal atrophy.

Aim 2: To understand the mechanism of tDCS by measuring tDCS-induced changes in network FC and GABA over the L_SMG. The investigators will carry out resting-state functional magnetic resonance imaging (rsfMRI), (MPRAGE), diffusion weighted imaging (DWI), perfusion imaging (pCASL), and magnetic resonance spectroscopy (MRS), before, after, and 3-months post-intervention.

Aim 3: To identify neural, cognitive, physiological, clinical and demographic characteristics (biomarkers) that predict sham, tDCS, and tDCS vs. sham effects on vSTM and related language tasks in PPA. The investigators will evaluate neural (functional and structural connectivity, cortical volume, neuropeptides, and perfusion), cognitive (memory, attention, executive) and language functions, clinical (severity), and demographic (age, gender) characteristics, and the investigators will analyze the effects on vSTM and other language/cognitive outcomes immediately after intervention and at 3 months post-intervention.