A multi-modal approach for the treatment of non-fluent/agrammatic variant of Primary Progressive Aphasia

Abstract

The non-fluent/agrammatic variant of primary progressive aphasia is a neurodegenerative disorder characterized by effortful language production and impaired comprehension of grammatically complex sentences. Recently, interest in non-pharmacological interventions has increased, particularly regarding techniques that allow for non-invasive brain stimulation, such as transcranial direct current stimulation. The main purpose of this study was to investigate whether the use of anodal transcranial direct current stimulation applied to the dorsolateral prefrontal cortex during individualized language training for 25 min a day at 5 days a week for 2 weeks would lead to significant oral naming improvements in patients with agrammatic variant of primary progressive aphasia. Specifically, we hypothesized that anodal transcranial direct current stimulation plus individualized language training may improve the oral naming of treated and untreated objects compared with both placebo transcranial direct current stimulation plus individualized language therapy and anodal transcranial direct current stimulation combined with computerized cognitive training. Forty-seven agrammatic variant of primary progressive aphasia patients were consecutively enrolled and randomized into one of three groups that received the following treatments: (i) anodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex during individualized language rehabilitation treatment; (ii) placebo transcranial direct current stimulation during individualized language rehabilitation treatment; or (iii) anodal transcranial direct current stimulation with computerized cognitive training. Clinical, neuropsychological and language assessments were recorded at baseline (T0), post-treatment (T1, 2 weeks) and at 12 weeks from T0 (T2). Magnetic resonance imaging data, functional magnetic resonance imaging data and blood samples were collected at T0 and T1. All of the groups demonstrated improvements in oral object naming at T1, with maintenance effects being observed at T2. At T1, the enhancement in the oral naming of treated and untreated objects was significantly greater in patients who underwent anodal transcranial direct current stimulation during individualized language rehabilitation treatment. There were no significant changes observed across the groups regarding the magnetic resonance imaging, functional magnetic resonance imaging or blood biochemical marker data. Our results support the beneficial effects of individualized language rehabilitation treatment in combination with anodal transcranial direct current stimulation in agrammatic variant of primary progressive aphasia patients.

Keywords: individualized language rehabilitation treatment; non-fluent/agrammatic variant of primary progressive aphasia; transcranial direct current stimulation.

Graphical Abstract

Figure 1

Consort flow diagram. Flow chart showing study subject enrolment and sample processing. tDCS, transcranial direct current stimulation; T0, baseline assessment.

Figure 2

Study design. (A) Timeline for the experimental protocol. (B) Treatment protocols: anodal tDCS over left DLPFC combined with an individualized language rehabilitation treatment (atDCS-Lang); placebo tDCS over left DLPFC during individualized language rehabilitation treatment (ptDCS-Lang); anodal tDCS over left DLPFC during computerized cognitive training (atDCS-Cog). (C) Current flow model of tDCS montage (anode over F3 and cathode over the right supraorbital area), using two 7 × 5 cm sponge pads represented in axial, sagittal and coronal views from the Male 1 model in the Soterix HD targets software (Soterix medical). Arrows represent the direction of current flow. cm, centimetre; DLPFC, dorsolateral prefrontal cortex; L, left; mA, milliampere; min, minutes; R, right; tDCS, transcranial direct current stimulation; T0, baseline assessment; T1, post-treatment assessment; T2, 12 weeks from T0 assessment; V/m, volt per metre.

Figure 3

Treated object naming task from IPNP (accuracy, %). Effects of treatments on treated object naming task from IPNP. ^GLMMs showed a significant interaction between group and time (P = 0.008). All groups improved from baseline (T0) to post-treatment (T1) (P < 0.001, Tukey-adjusted). The atDCS-Lang group exhibited greater improvement compared to atDCS-Cog (P = 0.0007) and ptDCS-Lang (P = 0.029). Gains were maintained at follow-up (T2) without significant group differences. Dashed lines represent individual trajectories over time, with colours indicating the tDCS group. Each point corresponds to the outcome variable at a specific time point (N = 135; 15 observations per group and time point). Raw scores mean are reported. Standard deviation between brackets. atDCS-Cog, anodal transcranial direct current stimulation during unstructured cognitive stimulation; atDCS-Lang, anodal transcranial direct current stimulation combined with individualized language rehabilitation treatment; IPNP, International Picture Naming Project; ptDCS-Lang, placebo transcranial direct current stimulation during individualized language rehabilitation treatment; SD, standard deviation.

Figure 4

Untreated object naming task from IPNP (accuracy, %). Effects of treatments on untreated object naming task from IPNP. ^GLMMs revealed a significant group × time interaction (P = 0.007). All groups improved from T0 to T1 (P < 0.001, Tukey-adjusted), with atDCS-Lang (P = 0.025) and atDCS-Cog (P = 0.058) showing greater gains than ptDCS-Lang. Improvements were sustained at follow-up (T2) without significant group differences. Dashed lines represent individual trajectories over time, with colours indicating the tDCS group. Each point corresponds to the outcome variable at a specific time point (N = 135; 15 observations per group and time point). Raw scores mean are reported. Standard deviation between brackets. atDCS-Cog, anodal transcranial direct current stimulation during unstructured cognitive stimulation; atDCS-Lang, anodal transcranial direct current stimulation combined with individualized language rehabilitation treatment; IPNP, International picture naming project; ptDCS-Lang, placebo transcranial direct current stimulation during individualized language rehabilitation treatment; SD, standard deviation.

Figure 5

Effects of treatments on BDNF and neurogranin levels. (A) BDNF and (B) neurogranin levels at baseline (T0) and post-treatment (T1) in the three groups of treatment (atDCS-Lang, ptDCS-Lang and atDCS-Cog). GLMMs, global time × group interaction (N = 45), BDNF P = 0.645, Neurogranin P = 0.243. Each point represents plasma BDNF or Neurogranin concentration. atDCS-Cog, anodal transcranial direct current stimulation during computerized cognitive training; atDCS-Lang, anodal transcranial direct current stimulation combined with individualized language rehabilitation treatment; BDNF, brain-derived neurotrophic factor; pg/ml, picograms per millilitre; ptDCS-Lang, placebo transcranial direct current stimulation during individualized language rehabilitation treatment.