Specificity in Generalization Effects of Transcranial Direct Current Stimulation Over the Left Inferior Frontal Gyrus in Primary Progressive Aphasia.

OBJECTIVES: Generalization (or near-transfer) effects of an intervention to tasks not explicitly trained are the most desirable intervention outcomes. However, they are rarely reported and even more rarely explained. One hypothesis for generalization effects is that the tasks improved share the same brain function/computation with the intervention task. We tested this hypothesis in this study of transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (IFG) that is claimed to be involved in selective semantic retrieval of information from the temporal lobes. MATERIALS AND METHODS: In this study, we examined whether tDCS over the left IFG in a group of patients with primary progressive aphasia (PPA), paired with a lexical/semantic retrieval intervention (oral and written naming), may specifically improve semantic fluency, a nontrained near-transfer task that relies on selective semantic retrieval, in patients with PPA. RESULTS: Semantic fluency improved significantly more in the active tDCS than in the sham tDCS condition immediately after and two weeks after treatment. This improvement was marginally significant two months after treatment. We also found that the active tDCS effect was specific to tasks that require this IFG computation (selective semantic retrieval) but not to other tasks that may require different computations of the frontal lobes. CONCLUSIONS: We provided interventional evidence that the left IFG is critical for selective semantic retrieval, and tDCS over the left IFG may have a near-transfer effect on tasks that depend on the same computation, even if they are not specifically trained. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02606422.

Impact of brain atrophy on tDCS and HD-tDCS current flow: a modeling study in three variants of primary progressive aphasia.

BACKGROUND: During transcranial direct current stimulation (tDCS), the amount and distribution of current that reaches the brain depends on individual anatomy. Many progressive neurodegenerative diseases are associated with cortical atrophy, but the importance of individual brain atrophy during tDCS in patients with progressive atrophy, including primary progressive aphasia (PPA), remains unclear. OBJECTIVE: In the present study, we addressed the question whether brain anatomy in patients with distinct cortical atrophy patterns would impact brain current intensity and distribution during tDCS over the left IFG. METHOD: We developed state-of-the-art, gyri-precise models of three subjects, each representing a variant of primary progressive aphasia: non-fluent variant PPA (nfvPPA), semantic variant PPA (svPPA), and logopenic variant PPA (lvPPA). We considered two exemplary montages over the left inferior frontal gyrus (IFG): a conventional pad montage (anode over F7, cathode over the right cheek) and a 4 × 1 high-definition tDCS montage. We further considered whether local anatomical features, specifically distance of the cortex to skull, can directly predict local electric field intensity. RESULTS: We found that the differences in brain current flow across the three PPA variants fall within the distribution of anatomically typical adults. While clustering of electric fields was often around individual gyri or sulci, the minimal distance from the gyri/sulci to skull was not correlated with electric field intensity. CONCLUSION: Limited to the conditions and assumptions considered here, this argues against a specific need to adjust the tDCS montage for these patients any more than might be considered useful in anatomically typical adults. Therefore, local atrophy does not, in isolation, reliably predict local electric field. Rather, our results are consistent with holistic head anatomy influencing brain current flow, with tDCS producing diffuse and individualized brain current flow patterns and HD-tDCS producing targeted brain current flow across individuals.

Sleep as a predictor of tDCS and language therapy outcomes.

STUDY OBJECTIVES: To determine whether sleep at baseline (before therapy) predicted improvements in language following either language therapy alone or coupled with transcranial direct current stimulation (tDCS) in individuals with primary progressive aphasia (PPA). METHODS: Twenty-three participants with PPA (mean age 68.13 ± 6.21) received written naming/spelling therapy coupled with either anodal tDCS over the left inferior frontal gyrus (IFG) or sham condition in a crossover, sham-controlled, double-blind design (ClinicalTrials.gov identifier: NCT02606422). The outcome measure was percent of letters spelled correctly for trained and untrained words retrieved in a naming/spelling task. Given its particular importance as a sleep parameter in older adults, we calculated sleep efficiency (total sleep time/time in bed x100) based on subjective responses on the Pittsburgh Sleep Quality Index (PSQI). We grouped individuals based on a median split: high versus low sleep efficiency. RESULTS: Participants with high sleep efficiency benefited more from written naming/spelling therapy than participants with low sleep efficiency in learning therapy materials (trained words). There was no effect of sleep efficiency in generalization of therapy materials to untrained words. Among participants with high sleep efficiency, those who received tDCS benefitted more from therapy than those who received sham condition. There was no additional benefit from tDCS in participants with low sleep efficiency. CONCLUSION: Sleep efficiency modified the effects of language therapy and tDCS on language in participants with PPA. These results suggest sleep is a determinant of neuromodulation effects.Clinical Trial: tDCS Intervention in Primary Progressive Aphasia https://clinicaltrials.gov/ct2/show/NCT02606422.

Treating lexical retrieval using letter fluency and tDCS in primary progressive aphasia: a single-case study.

Background: In early stages, individuals with Primary Progressive Aphasia (PPA) report language symptoms while scoring within norm in formal language tests. Early intervention is important due to the progressive nature of the disease. Method: We report a single case study of an individual with logopenic variant PPA (lvPPA). We tested whether letter fluency, used as a therapy task, can improve lexical retrieval when combined with tDCS to either the left inferior-frontal gyrus (IFG) or the left inferior parietal lobe (IPL), administered in two separate therapy phases separated by a wash-out period of three months. Outcomes and results: We observed increases in number of words retrieved during a letter fluency task in trained and untrained letters, when letter fluency therapy (LeFT) was administered with anodal tDCS. When LeFT was combined with left IFG stimulation, words produced in a letter fluency task were lower frequency and higher age of acquisition after treatment, compared to before treatment and there was also an increase in accuracy and response times in an untrained picture-naming task. Conclusions: The results indicate that letter fluency therapy combined anodal tDCS is effective in improving lexical retrieval, particularly when left IFG stimulation was used. Effects generalize beyond the trained task, albeit slowing down of responses in picture naming. This task may provide a useful clinical intervention strategy for patients with mild anomia, who are not challenged enough by traditional naming therapies.

Parkinsonics: A Randomized, Blinded, Cross-Over Trial of Group Singing for Motor and Nonmotor Symptoms in Idiopathic Parkinson Disease.

Introduction: Parkinson's disease (PD) frequently causes communication difficulties due to various voice impairments and there are few treatment options for vocal/communication complaints. We assessed the effects of weekly group singing on PD patients' objective vocal and motoric function, cognition, mood, self-efficacy, and quality of life. Methods: Thirty-two participants were randomly assigned to either a singing group or a facilitated discussion group weekly over 12 weeks. After 12 weeks, participants crossed over for an additional 12 weeks. Evaluations were performed at baseline and every six weeks for 30 weeks. Objective voice measures included volume/loudness (decibels), held vowel duration, jitter, shimmer, and harmonic-to-noise ratio. Additional outcome measures included patient-centered quality of life, voice-related quality of life, MDS-UPDRS, Montreal Cognitive Assessment, and questionnaires assessing depression, self-efficacy, and overall well-being. Results: Twenty-six participants (16 M/10F; Hoehn & Yahr stage 2.3 (range 2-3); and age 68.6 (55-89)) completed the study. Across participants in both groups (intention-to-treat analyses), there was significant improvement from baseline in average loudness on the Cookie Theft picture description at 24 weeks (end of interventions), corresponding with improved minimal reading volumes at 24 weeks and 30 weeks (end of study). Similarly, there were improvements in minimal loudness on Rainbow passage reading at 24 and 30 weeks. There were improvements observed in the Emotional Well-Being (mean delta -12.7 points, p = 0.037) and Body Discomfort (mean delta -18.6 points, p = 0.001) domains of the PDQ-39 from baseline to week 24 in the overall cohort and greater improvement in the Communication domain for Group S than Group D after 12 weeks of singing (delta -12.9 points, p = 0.016). Baseline differences between the participant groups (age, gender, Hoehn & Yahr stage, and several voice loudness measures) and observed improvements during the weekly discussion group period limited our ability to attribute all of the above results specifically to singing (per-protocol analyses). No significant changes in other assessed outcome measures were found. Conclusions: Weekly group singing may improve some aspects of conversational voice volume and quality of life in PD. Some improvements were sustained at least six weeks after interventions ended. Further investigations of the mechanism of benefit and randomized controlled studies (without crossover) to assess the longitudinal effects of singing in PD are necessary.

Selective Functional Network Changes Following tDCS-Augmented Language Treatment in Primary Progressive Aphasia.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has shown promising results when used as an adjunct to behavioral training in neurodegenerative diseases. However, the underlying neural mechanisms are not understood and neuroimaging evidence from pre/post treatment has been sparse. In this study, we examined tDCS-induced neural changes in a language intervention study for primary progressive aphasia (PPA), a neurodegenerative syndrome with language impairment as the primary clinical presentation. Anodal tDCS was applied to the left inferior frontal gyrus (LIFG). To evaluate the hypothesis that tDCS promotes system segregation, analysis focused on understanding tDCS-induced changes in the brain-wide functional network connectivity of the targeted LIFG. METHODS: Resting-state fMRI data were obtained from 32 participants with PPA before and after receiving a written naming therapy, accompanied either by tDCS or sham stimulation. We focused on evaluating changes in the global connectivity of the stimulated LIFG-triangularis (LIFG-tri) region given its important role in lexical processing. Global connectivity was indexed by the graph-theoretic measure participation coefficient (PC) which quantifies a region's level of system segregation. The values before and after treatment were compared for each condition (tDCS or Sham) as well as with age-matched healthy controls (n = 19). RESULTS: Higher global connectivity of the LIFG-tri before treatment was associated with greater dementia severity. After treatment, the tDCS group showed a significant decrease in global connectivity whereas the Sham group's did not change, suggesting specific neural effects induced by tDCS. Further examination revealed that the decrease was driven by reduced connectivity between the LIFG-tri and regions outside the perisylvian language area, consistent with the hypothesis that tDCS enhances the segregation of the language system and improves processing efficiency. Additionally, we found that these effects were specific to the LIFG-tri and not observed in other control regions. CONCLUSION: TDCS-augmented language therapy in PPA increased the functional segregation of the language system, a normalization of the hyper-connectivity observed before treatment. These findings add to our understanding of the nature of tDCS-induced neural changes in disease treatment and have applications for validating treatment efficacy and designing future tDCS and other non-invasive brain stimulation (NIBS) treatments.

Automatic Subtyping of Individuals with Primary Progressive Aphasia.

BACKGROUND: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists. OBJECTIVE: The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA. METHODS: In this paper, we present a machine learning model based on deep neural networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as to expert clinicians' classifications. RESULTS: The DNN model outperformed the other machine learning models as well as expert clinicians' classifications with 80% classification accuracy. Importantly, 90% of patients with nfvPPA and 95% of patients with lvPPA was identified correctly, providing reliable subtyping of these patients into their corresponding PPA variants. CONCLUSION: We show that the combined speech and language markers from connected speech productions can inform variant subtyping in patients with PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick, and inexpensive classification of patients with PPA.

Neural Correlates of Letter and Semantic Fluency in Primary Progressive Aphasia.

Verbal fluency (VF) is an informative cognitive task. Lesion and functional imaging studies implicate distinct cerebral areas that support letter versus semantic fluency and the understanding of neural and cognitive mechanisms underlying task performance. Most lesion studies include chronic stroke patients. People with primary progressive aphasia (PPA) provide complementary evidence for lesion-deficit associations, as different brain areas are affected in stroke versus PPA. In the present study we sought to determine imaging, clinical and demographic correlates of VF in PPA. Thirty-five patients with PPA underwent an assessment with letter and category VF tasks, evaluation of clinical features and an MRI scan for volumetric analysis. We used stepwise regression models to determine which brain areas are associated with VF performance while acknowledging the independent contribution of clinical and demographic factors. Letter fluency was predominantly associated with language severity (R2 = 38%), and correlated with the volume of the left superior temporal regions (R2 = 12%) and the right dorsolateral prefrontal area (R2 = 5%). Semantic fluency was predominantly associated with dementia severity (R2 = 47%) and correlated with the volume of the left inferior temporal gyrus (R2 = 7%). No other variables were significantly associated with performance in the two VF tasks. We concluded that, independently of disease severity, letter fluency is significantly associated with the volume of frontal and temporal areas whereas semantic fluency is associated mainly with the volume of temporal areas. Furthermore, our findings indicated that clinical severity plays a critical role in explaining VF performance in PPA, compared to the other clinical and demographic factors.

White Matter Integrity Predicts Electrical Stimulation (tDCS) and Language Therapy Effects in Primary Progressive Aphasia.

BACKGROUND: Transcranial direct current stimulation (tDCS), in conjunction with language therapy, improves language therapy outcomes in primary progressive aphasia (PPA). However, no studies show whether white matter integrity predicts language therapy or tDCS effects in PPA. OBJECTIVE: We aimed to determine whether white matter integrity, measured by diffusion tensor imaging (DTI), predicts written naming/spelling language therapy effects (letter accuracy on trained and untrained words) with and without tDCS over the left inferior frontal gyrus (IFG) in PPA. METHODS: Thirty-nine participants with PPA were randomly assigned to tDCS or sham condition, coupled with language therapy for 15 daily sessions. White matter integrity was measured by mean diffusivity (MD) and fractional anisotropy (FA) in DTI scans before therapy. Written naming outcomes were evaluated before, immediately after, 2 weeks, and 2 months posttherapy. To assess tDCS treatment effect, we used a mixed-effects model with treatment evaluation and time interaction. We considered a forward model selection approach to identify brain regions/fasciculi of which white matter integrity can predict improvement in performance of word naming. RESULTS: Both sham and tDCS groups significantly improved in trained items immediately after and at 2 months posttherapy. Improvement in the tDCS group was greater and generalized to untrained words. White matter integrity of ventral language pathways predicted tDCS effects in trained items whereas white matter integrity of dorsal language pathways predicted tDCS effects in untrained items. CONCLUSIONS: White matter integrity influences both language therapy and tDCS effects. Thus, it holds promise as a biomarker for deciding which patients will benefit from language therapy and tDCS.

Different patterns of functional network reorganization across the variants of primary progressive aphasia: a graph-theoretic analysis.

Primary progressive aphasia (PPA) is a neurodegenerative syndrome with three main variants (nonfluent, logopenic, semantic) that are identified primarily based on language deficit profiles and are associated with neurotopographically distinct atrophic patterns. We used a graph-theoretic analytic approach to examine changes in functional network properties measured with resting-state fMRI in all three PPA variants compared with age-matched healthy controls. All three variants showed a more segregated network organization than controls. To better understand the changes underlying the increased segregation, we examined the distribution of functional "hubs". We found that while all variants lost hubs in the left superior frontal and parietal regions, new hubs were recruited in different areas across the variants. In particular, both logopenic and semantic variants recruited significant numbers of hubs in the right hemisphere. Importantly, these functional characteristics could not be fully explained by local volume changes. These findings indicate that patterns of functional connectivity can serve as further evidence to distinguish the PPA variants, and provide a basis for longitudinal studies and for investigating treatment effects. This study also highlights the utility of graph-theoretic approaches in understanding the brain's functional reorganization in response to neurodegenerative disease.

Using narratives in differential diagnosis of neurodegenerative syndromes.

PURPOSE: Language decline has been associated with healthy aging and with various neurodegenerative conditions, making it challenging to differentiate among these conditions. This study examined the utility of linguistic measures derived from a short narrative language sample for 1) identifying language characteristics and cut-off scores to differentiate between healthy aging, Primary Progressive Aphasia (PPA), Mild Cognitive Impairment (MCI), and Alzheimer's dementia (AD); and 2) differentiating among PPA variants in which language is the primary impairment. METHOD: Participants were 25 neurologically healthy English speakers, 20 individuals with MCI, 20 with AD, and 26 with PPA (non-fluent/agrammatic N = 10, logopenic N = 9, semantic N = 7). Narrative language samples of the Cookie Theft Picture of persons with healthy aging, MCI and AD were retrospectively obtained from the DementiaBank database (https://talkbank.org/DementiaBank/) and PPA samples were obtained from an ongoing research study. The language samples were analyzed for fluency, word retrieval success, grammatical accuracy, and errors using automated and manual analysis methods. The sensitivity and specificity of various language measures was computed. RESULTS: Participants with PPA scored lower than neurologically healthy and MCI groups on fluency (words per minute and disfluencies), word retrieval (Correct Information Units and number of errors), and sentence grammaticality. PPA and AD groups did not differ on language measures. Agrammatic PPA participants scored lower than logopenic and semantic PPA groups on several measures, while logopenic and semantic PPA did not differ on any measures. CONCLUSION: Measures derived from brief language samples and analyzed using mostly automated methods are clinically useful in differentiating PPA from healthy aging and MCI, and agrammatic PPA from other variants. The sensitivity and specificity of these measures is modest and can be improved when coupled with clinical presentation.

Brain volumes as predictors of tDCS effects in primary progressive aphasia.

The current study aims to determine the brain areas critical for response to anodal transcranial direct current stimulation (tDCS) in PPA. Anodal tDCS and sham were administered over the left inferior frontal gyrus (IFG), combined with written naming/spelling therapy. Thirty people with PPA were included in this study, and assessed immediately, 2 weeks, and 2 months post-therapy. We identified anatomical areas whose volumes significantly predicted the additional tDCS effects. For trained words, the volumes of the left Angular Gyrus and left Posterior Cingulate Cortex predicted the additional tDCS gain. For untrained words, the volumes of the left Middle Frontal Gyrus, left Supramarginal Gyrus, and right Posterior Cingulate Cortex predicted the additional tDCS gain. These findings show that areas involved in language, attention and working memory contribute to the maintenance and generalization of stimulation effects. The findings highlight that tDCS possibly affects areas anatomically or functionally connected to stimulation targets.

Cognitive and language performance predicts effects of spelling intervention and tDCS in Primary Progressive Aphasia.

Predictors of treatment effects allow individual tailoring of treatment characteristics, thereby saving resources and optimizing outcomes. Electrical stimulation coupled with language intervention has shown promising results in improving language performance in individuals with Primary Progressive Aphasia (PPA). The current study aimed to identify language and cognitive variables associated with response to therapy consisting of language intervention combined with transcranial direct current stimulation (tDCS). Forty individuals with PPA received written naming/spelling intervention combined with anodal tDCS or Sham, using a between-subjects, randomized design, with intervention delivered over a period of 3 weeks. Participants were assessed using a battery of neuropsychological tests before and after each phase. We measured letter accuracy during spelling of trained and untrained words, before, immediately after, 2 weeks, and 2 months after therapy. We used step-wise regression methods to identify variables amongst the neuropsychological measures and experimental factors that were significantly associated with therapy outcomes at each time-point. For trained words, improvement was related to pre-therapy scores, in RAVLT (5 trials sum), pseudoword spelling, object naming, digit span backward, spatial span backward and years post symptom onset. Regarding generalization to untrained words, improvement in spelling was associated with pseudoword spelling, RAVLT proactive interference, RAVLT immediate recall. Generalization effects were larger under tDCS compared to Sham at the 2-month post training measurement. We conclude that, for trained words, patients who improve the most are those who retain for longer language skills such as sublexical spelling processes (phoneme-to-grapheme correspondences) and word retrieval, and other cognitive functions such as executive functions and working memory, and those who have a better learning capacity. Generalization to untrained words occurs through improvement in knowledge of phoneme-to-grapheme correspondences. Furthermore, tDCS enhances the generalizability and duration of therapy effects.

Understanding the Role of Systemic Inflammation in Alzheimer's Disease.

Human and animal studies suggest that inflammation occurring outside the central nervous system (systemic inflammation) may play a key role in promoting neurodegeneration, Alzheimer's disease pathology, and cognitive decline in older adults. Systemic inflammation, which is marked by increased blood levels of circulating proinflammatory cytokines and chemokines, may occur as a result of events such as infection, chronic disease, and physical and psychological stress, but may also occur outside the context of these conditions as a result of subclinical processes such as cellular senescence. Proinflammatory cytokines within the body can promote a proinflammatory environment in the central nervous system by crossing the blood-brain barrier, signaling through endothelial cells or circumventricular organs, and by stimulating the vagus nerve, which signals the detection of inflammatory proteins via direct afferent connections to the brain stem. Through each of these routes, systemic inflammation is believed to induce reactive, proinflammatory microglia and astrocytic phenotypes which can promote tau hyperphosphorylation, ß-amyloid oligomerization, complement activation, and the breakdown of neurotransmitters into potentially harmful bioactive metabolites. Together, these molecular changes are believed initiate or exacerbate neurodegenerative processes that can eventually lead to cognitive decline and dementia in vulnerable older adults.

The Role of Word Properties in Performance on Fluency Tasks in People with Primary Progressive Aphasia.

People with primary progressive aphasia (PPA) present language difficulties that require lengthy assessments and follow-ups. Despite individual differences, people with PPA are often classified into three variants that present some distinctive language difficulties. We analyzed the data of 6 fluency tasks (i.e., "F", "A", "S", "Fruits", "Animals", "Vegetables"). We used random forests to pinpoint relevant word properties and error types in the classification of the three PPA variants, conditional inference trees to indicate how relevant variables may interact with one another and ANOVAs to cross-validate the results. Results indicate that total word count helps distinguish healthy individuals (N = 10) from people with PPA (N = 29). Furthermore, mean familiarity differentiates people with svPPA (N = 8) from people with lvPPA (N = 10) and nfvPPA (N = 11). No other word property or error type was relevant in the classification. These results relate to previous literature, as familiarity effects have been reported in people with svPPA in naming and spontaneous speech. Also, they strengthen the relevance of using familiarity to identify a specific group of people with PPA. This paper enhances our understanding of what determines word retrieval in people with PPA, complementing and extending data from naming studies.

Reductions in GABA following a tDCS-language intervention for primary progressive aphasia.

Transcranial direct current stimulation (tDCS) has shown efficacy in augmenting the effects of language therapy in primary progressive aphasia (PPA). The mechanism of action of tDCS is not understood, but preliminary work in healthy adults suggests it modulates γ-aminobutyric acid (GABA) levels to create an environment optimal for learning. It is unknown if this proposed mechanism translates to aging or neurodegenerative conditions. This study tested the hypothesis that tDCS reduces GABA at the stimulated tissue in PPA. We applied GABA-edited magnetic resonance spectroscopy to quantify GABA levels before and after a sham-controlled tDCS intervention with language therapy in PPA. All participants showed improvements but those receiving active tDCS showed significantly greater language improvements compared to sham both immediately after the intervention and at 2-month follow-up. GABA levels in the targeted tissue decreased from baseline after the intervention and remained decreased 2 months after the intervention. This work supports the hypothesis that tDCS modulates GABAergic inhibition to augment learning and is clinically useful for PPA combined with language therapy.

Written Verb Naming Improves After tDCS Over the Left IFG in Primary Progressive Aphasia.

Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique, is an effective adjunct to naming treatments in post-stroke aphasia and primary progressive aphasia (PPA). Enhanced performance in oral and written naming and spelling of nouns with tDCS has been quantified in detail, but it is not known whether it is effective for verb treatment in PPA. We addressed the question of whether performance in naming and spelling of verbs can be augmented with anodal tDCS over the left inferior frontal gyrus (IFG). We compared tDCS coupled with oral and written verb naming/spelling treatment with oral and written verb naming/spelling treatment alone. In a double-blind, sham-controlled, crossover design, 11 participants with logopenic or non-fluent variant PPA received approximately 15 consecutive sessions of anodal tDCS and sham over the left IFG coupled with oral and written verb-naming + spelling treatment. Written verb-naming performance improved significantly more for trained verbs in the tDCS than the sham condition. Importantly, tDCS effects generalized to untrained items for written verb naming and were significant even at 2 months post-treatment. We conclude that tDCS over the left IFG can improve written verb naming and spelling in PPA.

"The effect of tDCS on functional connectivity in primary progressive aphasia" NeuroImage: Clinical, volume 19 (2018), pages 703-715.

Transcranial direct current stimulation (tDCS) is an innovative technique recently shown to improve language outcomes even in neurodegenerative conditions such as primary progressive aphasia (PPA), but the underlying brain mechanisms are not known. The present study tested whether the additional language gains with repetitive tDCS (over sham) in PPA are caused by changes in functional connectivity between the stimulated area (the left inferior frontal gyrus (IFG)) and the rest of the language network. We scanned 24 PPA participants (11 female) before and after language intervention (written naming/spelling) with a resting-state fMRI sequence and compared changes before and after three weeks of tDCS or sham coupled with language therapy. We correlated changes in the language network as well as in the default mode network (DMN) with language therapy outcome measures (letter accuracy in written naming). Significant tDCS effects in functional connectivity were observed between the stimulated area and other language network areas and between the language network and the DMN. TDCS over the left IFG lowered the connectivity between the above pairs. Changes in functional connectivity correlated with improvement in language scores (letter accuracy as a proxy for written naming) evaluated before and after therapy. These results suggest that one mechanism for anodal tDCS over the left IFG in PPA is a decrease in functional connectivity (compared to sham) between the stimulated site and other posterior areas of the language network. These results are in line with similar decreases in connectivity observed after tDCS over the left IFG in aging and other neurodegenerative conditions.

The Role of Language Severity and Education in Explaining Performance on Object and Action Naming in Primary Progressive Aphasia.

Despite the common assumption that atrophy in a certain brain area would compromise the function that it subserves, this is not always the case, especially in complex clinical syndromes such as primary progressive aphasia (PPA). Clinical and demographic information may contribute to PPA phenotypes and explain the manifested impairments better than atrophy. In the present study, we asked how much variance of the object and action naming impairments observed in PPA may be attributed to atrophy in the language network alone vs. additional clinical and demographic factors including language severity and education. Thirty-nine participants with PPA underwent magnetic resonance imaging (MRI) for volumetric analysis and a complete neuropsychological examination, including standardized tests of object and action naming. We used stepwise regression models to compare atrophy (volumetric model) to clinical/demographic variables (clinical-demographic model) for naming objects and actions. The clinical-demographic model was the best-fit model that explained the largest amount of variance in both object and action naming. Brain volume measurements alone explained little variance in both object and action naming. Clinical factors, particularly language severity, and demographic factors, particularly education, need to be considered in conjunction with brain volumes in PPA. The present study emphasizes the complexity of PPA as a syndrome and provides an example of how volumetric, clinical and demographic factors may interact in determining naming performance/deterioration.

Electrical brain stimulation in different variants of primary progressive aphasia: A randomized clinical trial.

INTRODUCTION: Transcranial direct current stimulation (tDCS) has been recently shown to improve language outcomes in primary progressive aphasia (PPA) but most studies are small and the influence of PPA variant is unknown. METHODS: Thirty-six patients with PPA participated in a randomized, sham-controlled, double-blind, within-subject crossover design for 15 daily sessions of stimulation coupled with written naming/spelling therapy. Outcome measures were letter accuracy of treated and untreated words immediately after and at 2 weeks and 2 months posttreatment. RESULTS: tDCS treatment was more effective than sham: gains for treated words were maintained 2 months posttreatment; gains from tDCS also generalized to untreated words and were sustained 2 months posttreatment. Different effects were obtained for each PPA variant, with no tDCS advantage for semantic variant PPA. DISCUSSION: The study supports using tDCS as an adjunct to written language interventions in individuals with logopenic or nonfluent/agrammatic PPA seeking compensatory treatments in clinical settings.