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Language intervention has been shown to critically affect the course of post-stroke language rehabilitation. Interventions at early or chronic stages (either by reperfusion, speech-language therapy or tDCS) have dramatically improved outcomes in language post-stroke rehabilitation. Little is known, however, about interventions in neurodegerative diseases and the changes in neural substrates they may induce. It has been shown that language therapy is indeed beneficial and improves language outcomes, both with behavioral interventions and more recently with tDCS for longer lasting and more generalizable effects even in PPA(Cotelli et al., 2014; Tsapkini, Frangakis, Gomez, Davis, & Hillis, 2014). However, it has not been addressed how this is instantiated in the brain. In this paper we evaluate the effects of tDCS in 18 participants with PPA who received both sham and tDCS coupled with language therapy. Our primary aim was to evaluate the effects of intervention and determine the neural correlates of tDCS vs. sham interventions that led to improved language outcomes using resting-state fMRI (rs-fMRI). Method: Eighteen patients diagnosed with PPA underwent written or oral language production intervention with and without tDCS (sham) in a within-subjects cross-over design. Participants received treatment for 2 weeks, 10 sessions for each condition. Each condition was separated by 3 months. Resting-state fMRI data were obtained on the first treatment condition from 13 participants who underwent written language intervention at 3 time-points: before, after and 2-months post-intervention. Participants were pseudo-randomly assigned in either tDCS or sham condition first in a between-subjects design. Results: First, we replicated our previous results obtained with fewer participants: all improved in both tDCS and sham conditions on trained items. Generalization of treatment on untrained items was significant only in tDCS condition. Therapy gains lasted longer in tDCS condition as well. Second, preliminary analyses of rs-fMRI show changes of functional connectivity between written language areas in the tDCS and sham conditions. Conclusions: tDCS represents an increasingly valuable treatment option in language rehabilitation even in neurodegeneration. Late intervention is as beneficial as early intervention but improvement seems more dramatic in early cases. Different possibilities are discussed: tDCS may indeed change the course of the disease, i.e., it may slow down the rate of decline or, language improvement due to tDCS (or delay in language deterioration due to the course of the disease) may hold the spread of decline in other cognitive functions, thus, early interventions appear more beneficial. The correlation between functional connectivity and language production outcomes is expected to shed light on how tDCS works in the brains of people with a neurodegenerative disease. Implications of functional connectivity changes between language areas involved in the targeted language function will inform further interventions.

We review rationale, challenges, study designs, reported results, and future directions in the use of transcranial direct cranial stimulation (tDCS) in neurodegenerative disease, focusing on treatment of spelling in primary progressive aphasia (PPA). Rationale Evidence from both animal studies and human studies indicates that anodal and cathodal tDCS over the brain result in a temporary change in membrane potentials, reducing the threshold for long-term potentiation of neurons in the affected area. This may allow unaffected brain regions to assume functions of diseased regions. Challenges Special challenges in treating individuals with progressive conditions include altered goals of treatment and the possibility that participants may accumulate new deficits over the course of the treatment program that interfere with their ability to understand, retain, or cooperate with aspects of the program. The most serious challenge – particularly for single case designs - is that there may be no stable baseline against which to measure change with treatment. Thus, it is essential to demonstrate that treatment results in a statistically significant change in the slope of decline or improvement. Therefore, demonstration of a significant difference between tDCS and control (sham) requires either a large number of participants or a large effect size. Designs The choice of a treatment design reflects these limitations. Group studies with a randomized, double-blind, sham control trial design (without cross-over) provide the greatest power to detect a difference between intervention and control conditions, with the fewest participants. A cross-over design, in which all participants (from 1 to many) receive both active and sham conditions, in randomized order, requires a larger effect size for the active condition relative to the control condition (or little to no maintenance of treatment gains or carry-over effect) to show significant differences between treatment and control conditions. Stimulation site The stimulation site may be chosen on the basis of the most atrophied area (e.g. homologous to that area) or an area of activation based on fMRI. Alternatively, one can select the site on the basis of the language process to be treated, or select from a set of sites on the basis of the language process to be treated, and exclude sites where there is significant atrophy. Observations to Date While several studies have incorporated tDCS in treatment of recognition memory and in Alzheimer’s disease, effective use of tDCS to treat language in neurodegenenerative disease has primarily been in primary progressive aphasia (PPA). We will illustrate its use in aphasia by reporting results of a series of single case cross-over studies of spelling therapy plus left inferior frontal anodal tDCS versus spelling therapy plus sham. Results indicate that both conditions result in temporary improvement of spelling, but significantly greater maintenance of treatment gains and generalization to untrained stimuli and tasks after tDCS condition relative to sham. Future Directions Future studies must determine the most effective way to improve maintenance of treatment results and determine the mechanisms by which tDCS augments language therapy.

Introduction The local-global dimension (Navon, 1977) has been studied extensively in healthy controls and preference for globally processed stimuli has been validated in both the visual and auditory modalities. Critically, the local-global dimension has an inherent interference resolution component, a type of cognitive control, and left-prefrontal-cortex-damaged (LPFC) individuals have exhibited inability to override habitual response behaviors in item recognition tasks that involve representational interference (Hamilton & Martin, 2005; Novick, Trueswell, & Thompson-Schill, 2005). However, very little is known about how the local-global attentional dimension affects LPFC-damaged individuals with aphasia in language and non-language domains that involve cognitive control mechanisms. Methods Eight patients with damage in the left PFC and twenty age- and education-matched language-unimpaired adults have participated in the study. Non-verbal tasks included an online Global-Local Identification task (designed after Navon, 1977) asking from participants to identify global geometrical shapes, which were made up of smaller (local) geometrical configurations while inhibiting local ones, and vice versa. In congruent trials, local and global shapes coincided whereas in incongruent trials they did not. Apart from the local and global condition, the task included a mixed local-global condition, in which participants were asked to identify global and local shapes interchangeably. Participants’ updating functions were independently measured by an online 2-back digit task where individuals were presented with digit sequences and were asked to respond by pressing a pre-specified key once a digit matched the digit occurring two digits earlier. The study also involved four online language tasks: (a) a task testing the interpretation of pronouns (Peristeri & Tsimpli, 2013) in globally ambiguous sentential contexts, (b) a task testing the interpretation of homophones in sentences requiring global processing, (c) a task testing the participants’ sensitivity to local, grammatical gender conflicts of single words in a picture-word interference task, and, (d) a task testing participants’ sensitivity to local orthographic violations in the stems and suffixes of single words in a semantic judgment task. Results In the Global-Local Identification task, LPFC-damaged patients with non-fluent aphasia performed more poorly in both accuracy (42% correct) and RTs on the local incongruent trials—where identification of the local shape presupposed inhibition of the global configuration—than any other global incongruent or congruent category. Controls were slower (but accurate) in local incongruent trials. On the other hand, PFC-damaged patients (along with controls) performed at ceiling level in the 2-back digit task, thus, indicating no deficit in their updating abilities. With respect to the language tasks, the patients performed more poorly in RTs in the tasks tapping on the integration of local cues relative to the tasks where conflict resolution was critically dependent on the parser’s sensitivity to global context. Discussion Overall, the local-global dimension seems to critically influence the performance of LPFC-damaged individuals with non-fluent aphasia in both language and non-language domains. A possible interpretation is that participants were able to override conflict more easily in tasks tapping on global than local processing. Broader implications for distinct types of inhibitory processes depending on the level of processing will be discussed.

Introduction: Spelling impairments are one of the first deficits that occur early in PPA and can usually predict the variant of PPA in which the patient may progress (Sepelyak et al., 2011). PPA is a neurodegenerative disease that affects people relatively early in life (between 55-65 years) and therefore it is important to find ways to alleviate the symptoms or impede the degree of degeneration. We present and discuss new data indicating that a neuromodulatory treatment, using transcranial direct current stimulation (tDCS) combined with a spelling intervention, shows promise for maintaining or even improving language abilities in PPA. The aim of this research is to determine whether tDCS plus language therapy is more effective than language therapy alone in treating written language deficits in PPA. Methods: Eight PPA participants underwent anodal tDCS or sham plus spelling intervention in a randomized order using a within-subject cross-over design. They were evaluated before, after, and at 2 weeks and 2 months post-intervention. Spelling intervention varied for each participant according to the main spelling deficit: 3 patients had phoneme-to-grapheme conversion (PGC) intervention, 2 had lexical intervention and 3 had advanced PGC intervention (combined with written fluency and PGC practice). Four more patients have already finished the first period of stimulations (ether sham or tDCS) and all their other sessions and evaluations will be completed in the next couple months. Analyses-Results: We analyzed the existing set of full data using both within-subject analyses (McNemar tests) and across-subjects analyses while taking into account carry-over effects. We evaluated therapy effects by the Generalized Estimating Equation approach (Liang & Zeger, 1986). All participants showed improvement in spelling after spelling intervention in trained items (with either sham or tDCS). There was, however, a significant improvement for untrained items only in the tDCS plus language therapy condition compared to sham at all follow-up intervals but mostly at 2 months post-intervention. Conclusions: We discuss these results with emphasis to the particular challenges of this method. Neuromodulation with tDCS offers promise as a means of augmenting language therapy to improve written language function, at least short-term, in PPA. The consistent finding of generalization of treatment benefits to untreated items and the superior sustainability of treatment effects with tDCS justifies further investigations. Possible explanations of brain mechanisms involved and current efforts in investigating them are also discussed.