HDtDCS in Logopenic Variant PPA: Effects on Language and Neural Mechanisms

High-Definition Transcranial Direct Current Stimulation (HD-tDCS) in Logopenic Variant Primary Progressive Aphasia (lvPPA): Effects on Language and Neural Mechanisms

This study aims to evaluate the effectiveness of a therapy called High-Definition Transcranial Direct Current Stimulation (HD-tDCS) for the treatment of the language deficits experienced by people with a type of Primary Progressive Aphasia. This study uses a combination of brain imaging, language assessment, language training sessions, and HD-tDCS therapy as well as placebo therapy sessions.

The logopenic variant of Primary Progressive Aphasia (lvPPA) is an untreatable neurodegenerative disorder that is often referred to as the 'language form' of Alzheimer's Disease (AD). Transcranial Direct Current Stimulation (tDCS) has emerged as a safe and potentially effective tool that appears to enhance language production when delivered during language training. This technology provides a critical opportunity to conduct disease intervention. In this study, the investigators will test the hypothesis that High-Definition tDCS (HD-tDCS) will improve performance on language tasks by increasing functional connectivity and by regulating abnormal neuronal oscillatory patterns. The rationale for this project is that a determination of the therapeutic efficacy and the associated neural mechanisms of HD-tDCS in lvPPA is likely to offer a scientific framework whereby new stimulation parameters, conditions, and target sites can be deciphered. This study will test the hypothesis that HD-tDCS will improve performance on language tasks by increasing functional connectivity and by regulating abnormal neuronal oscillatory patterns. The language performance and functional connectivity changes will be determined in a randomized, double-blind, sham-controlled crossover manner, in which a stimulation of up to 2mA in the targeted cortical tissue or sham is administered to 20 lvPPA subjects age 45 years and older. The order of treatments is counterbalanced in a within-subject crossover design. In brief, study participants will receive sham during one treatment period and stimulation during the other treatment period.

Adult, Primary Progressive Aphasia, High-definition Transcranial Direct Current Stimulation, HD-tDCS, Language, Logopenic, Magnetic Resonance Imaging, MRI, Magnetoencephalography, MEG, Brain, Aphasia

This is a randomized, double-blind, sham-controlled trial in which stimulation or sham will be administered to 20 subjects over the age of 45 years, with the order of treatments counterbalanced in a within-subject crossover design. Stimulation and sham sessions last 20 minutes and occur for 10 days over a 2-week period.

An unblinded member of the study team will randomize participants to the treatment conditions. Study Group assignment will be based on random number generation (in blocks of 4) followed by the creation of numbered envelopes. Participants and the study team members involved in language training, tDCS delivery, and assessment of outcomes will be blind to the treatment received.

Subjects receive High Dose transcranial Direct Current Stimulation (HD-tDCS) lasting 20 minutes at an electric current intensity of up to 2mA in the left posterior temporo-parietal cortex (TPC). Stimulation sessions are delivered once a day (QD) for a total of 10 sessions over 2 weeks (Monday-Friday). After a washout period of 16 weeks, subjects receive Sham sessions (no electric current) once a day (QD) for a total of 10 sessions over 2 weeks (Monday-Friday).

Subjects receive Sham sessions (no electric current) once a day (QD) for a total of 10 sessions over 2 weeks (Monday-Friday). After a washout period of 16 weeks, subjects receive High Dose transcranial Direct Current Stimulation (HD-tDCS) lasting 20 minutes at an electric current intensity of up to 2mA in the left posterior temporo-parietal cortex (TPC). Stimulation sessions are delivered once a day (QD) for a total of 10 sessions over 2 weeks (Monday-Friday).

Language Performance on seven cognitive assessments: Picture Naming, Letter & Category Fluency, Digit Span Test, Phonological Short-term Memory Test, Word and non-word rhyme matching, Spontaneous Speech Sample, and Communicative Effectiveness Index.

Language performance changes as assessed at baseline and after tDCS stimulation procedures as measured by the seven assessments listed above. Scores across all tests within the language battery will be combined into one composite measure to facilitate assessment of overall language performance across domains. All seven scores will be normalized to a Z-score by transforming individual raw test scores according to the mean and standard deviation of the scores for all subjects. Then, Z-scores of each test will be averaged to obtain an individual composite language Z-score (McConathey et al., 2017). We will employ age, years of education, gender, and gray matter (GM) volume as time-invariant covariates to obtain residual variables to determine the LG changes due to stimulation. We will model the LG score as a function of these nuisance regressors. This regression will be performed using all the data (i.e., all subjects, all groups, and all times).

Changes in brain functional connectivity as assessed at baseline and after tDCS stimulation as measured on fMRI

Changes in abnormal patterns of neuronal frequencies and synchronizations as assessed at baseline and after tDCS stimulation procedures as measured on rsMEG. Connectivity between all ROI-pairs (Region of Interest) will be calculated in the theta (4-8 Hz), alpha (8-12 Hz), beta (13-30 Hz), and low-gamma (30-55 Hz) frequency bands using three different metrics: coherence (COH), phase lag index (PLI), and debiased weighted phase lag index (d-wPLI). Mean connection strengths within 3 intra-hemispheric language-specific ROI-groups, and those between all intra-hemispheric ROIs will be computed. We will also compute mean connection strengths between language ROI-groups and all remaining brain ROIs, and those between each hemispheric ROI and all other brain ROIs.

Inclusion Criteria: Diagnosed with language variant Primary Progressive Aphasia (lvPPA) subtype, defined as either clinical lvPPA or imaging-supported lvPPA in accordance with the most recent diagnostic criteria (Mesulam., 2001; Gorno-Tempini et al., 2011). Fluent in English. 45 years of age or older. Structural brain MRI performed within 3 years prior to enrollment. Exclusion Criteria: Severe cognitive, auditory or visual impairments that would preclude cognitive testing. Presence of major untreated or unstable psychiatric disease. A chronic medical condition that is not treated or is unstable. The presence of cardiac stimulators or pacemakers. Any metal implants in the skull Contraindications to MRI History of seizures History of dyslexia or other developmental learning disabilities.

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