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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. 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 (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 ( = 19). 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. 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.

Transcranial Direct Current Stimulation may be a useful neuromodulation tool for enhancing the effects of speech and language therapy in people with aphasia, but research so far has focused on monolinguals. We present the effects of 9 sessions of anodal cerebellar tDCS (ctDCS) coupled with language therapy in a bilingual patient with chronic post-stroke aphasia caused by left frontal ischemia, in a double-blind, sham-controlled within-subject design. Language therapy was provided in his second language (L2). Both sham and anodal treatment improved trained picture naming in the treated language (L2), while anodal ctDCS in addition improved picture naming of untrained items in L2 and his first language, L1. Picture description improved in L2 and L1 after anodal ctDCS, but not after sham.

Transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (IFG) was found to improve oral and written naming in post-stroke and primary progressive aphasia (PPA), speech fluency in stuttering, a developmental speech-motor disorder, and apraxia of speech (AOS) symptoms in post-stroke aphasia. This paper addressed the question of whether tDCS over the left IFG coupled with speech therapy may improve sound duration in patients with apraxia of speech (AOS) symptoms in non-fluent PPA (nfvPPA/AOS) more than sham. Eight patients with non-fluent PPA/AOS received either active or sham tDCS, along with speech therapy for 15 sessions. Speech therapy involved repeating words of increasing syllable-length. Evaluations took place before, immediately after, and two months post-intervention. Words were segmented into vowels and consonants and the duration of each vowel and consonant was measured. Segmental duration was significantly shorter after tDCS compared to sham and tDCS gains generalized to untrained words. The effects of tDCS sustained over two months post-treatment in trained and untrained sounds. Taken together, these results demonstrate that tDCS over the left IFG may facilitate speech production by reducing segmental duration. The results provide preliminary evidence that tDCS may maximize efficacy of speech therapy in patients with nfvPPA/AOS.

A variety of tDCS approaches has been used to investigate the potential of tDCS to improve language outcomes, or slow down the decay of language competences caused by Primary Progressive Aphasia (PPA). The employed stimulation protocols and study designs in PPA are generally speaking similar to those deployed in post-stroke aphasic populations. These two etiologies of aphasia however differ substantially in their pathophysiology, and for both conditions the optimal stimulation paradigm still needs to be established. A systematic review was done and after applying inclusion and exclusion criteria, 15 articles were analyzed focusing on differences and similarities across studies especially focusing on PPA patient characteristics (age, PPA variant, language background), tDCS stimulation protocols (intensity, frequency, combined therapy, electrode configuration) and study design as recent reviews and group outcomes for individual studies suggest tDCS is an effective tool to improve language outcomes, while methodological approach and patient characteristics are mentioned as moderators that may influence treatment effects. We found that studies of tDCS in PPA have clinical and methodological and heterogeneity regarding patient populations, stimulation protocols and study design. While positive group results are usually found irrespective of these differences, the magnitude, duration and generalization of these outcomes differ when comparing stimulation locations, and when results are stratified according to the clinical variant of PPA. We interpret the results of included studies in light of patient characteristics and methodological decisions. Further, we highlight the role neuroimaging can play in study protocols and interpreting results and make recommendations for future work.

BackgroundDuring 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.ObjectiveIn 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.MethodWe 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.ResultsWe 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.ConclusionLimited 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.

Dissociating Primary Progressive Aphasia (PPA) from Mild Cognitive Impairment (MCI) is an important, yet challenging task. Given the need for low-cost and time-efficient classification, we used low-density electroencephalography (EEG) recordings to automatically classify PPA, MCI and healthy control (HC) individuals. To the best of our knowledge, this is the first attempt to classify individuals from these three populations at the same time. We collected three-minute EEG recordings with an 8-channel system from eight MCI, fourteen PPA and eight HC individuals. Utilizing the Relative Wavelet Entropy method, we derived (i) functional connectivity, (ii) graph theory metrics and extracted (iii) various energy rhythms. Features from all three sources were used for classification. The k-Nearest Neighbor and Support Vector Machines classifiers were used. A 100% individual classification accuracy was achieved in the HC-MCI, HC-PPA, and MCI-PPA comparisons, and a 77.78% accuracy in the HC-MCI-PPA comparison. We showed for the first time that successful automatic classification between HC, MCI and PPA is possible with short, low-density EEG recordings. Despite methodological limitations of the current study, these results have important implications for clinical practice since they show that fast, low-cost and accurate disease diagnosis of these disorders is possible. Future studies need to establish the generalizability of the current findings with larger sample sizes and the efficient use of this methodology in a clinical setting.

Background/Objectives: Executive function (EF) impairments are found in a variety of neurodegenerative disorders, including in Primary Progressive Aphasia (PPA), which is primarily characterized by language impairments. The goal of this preliminary investigation was to evaluate the hypothesis that, by targeting domain-general EFs, domain-specific functions—specifically, language processing—might also be improved in this population. Methods: This case series included four Greek-speaking individuals with PPA who underwent behavioral and neurostimulation treatment daily for 15 consecutive sessions. Behavioral treatment was performed through Computerized Cognitive Training (CCT) that targeted various EF functions. Neurostimulation treatment included alpha-rhythm transcranial alternating current stimulation (tACS) over the left dorsolateral prefrontal cortex (DLPFC), previously implicated in EF functioning. EF and language performance was assessed before (pre-) and after (post-) treatment and was also compared against the performance of healthy control individuals. Results: The pre- to post-treatment comparisons showed improvements primarily in EF functions, with heterogeneous improvements in language functions across the four cases. Except for one task (N-back), in which all four patients showed numerical improvement, the pattern of numerical gains differed across patients. Conclusions: While the treatment protocol targeted EF functioning, improvements were found for both EF and language processes (albeit more variable across patients). These results support the hypothesis that improvement in domain-general functions may lead to improvements in domain-specific functions as well. These preliminary findings can be used as guiding evidence for the design of future, large-scale clinical trials that will allow us to generalize conclusions to the broader PPA population.

Primary progressive aphasia (PPA) is a neurological syndrome characterized by the gradual deterioration of language capabilities. Due to its neurodegenerative nature, PPA is marked by a continuous decline, necessitating ongoing and adaptive therapeutic interventions. Recent studies have demonstrated that behavioral therapies, particularly when combined with neuromodulation techniques such as transcranial direct current stimulation (tDCS), can improve treatment outcomes, including the long-term maintenance and generalization of therapeutic effects. However, there has yet to be a phase II multisite study examining the efficacy of tDCS in individuals with PPA. This paper reports the methods and analyses for the clinical trial NCT05386394. A total of 120 adults with non-fluent and logopenic variant PPA will receive a novel spoken Naming and Spelling (NaSp), individuals with semantic variant PPA will be excluded from this trial. Participants will receive NASP therapy over two periods of 3 weeks (Monday through Friday, for a total of 15 non-consecutive days) combined with anodal (a-tDCS) and sham tDCS (s-tDCS). They will be randomly allocated to receive a-tDCS either during the first or second intervention period. The study will be conducted at four sites across the United States and Canada. Outcome measures will be recorded immediately before and after each intervention period, as well as 3 months after each period. Primary outcome measures will be the change in phonemic accuracy in spoken picture naming and letter accuracy in spelling for trained nouns and verbs. Changes from the a-tDCS and s-tDCS periods will be compared to determine the efficacy of tDCS. Primary outcomes will be analyzed using statistical methods that account for repeated measures within participants (namely generalized estimating equations). A significant adjuvant effect of tDCS will be determined if differences in phonemic accuracy and/or letter accuracy immediately following a-tDCS intervention and/or at the 3-month follow-up are greater (at p < 0.05) than those of the s-tDCS intervention. This trial is the first multisite, fully powered, randomized, double-blind, sham-controlled, crossover study of the effectiveness of tDCS as an adjuvant to behavioral treatment for spoken naming and spelling deficits in individuals with PPA. Specific challenges in designing the protocol are considered.

Background and objectives The two variants of primary progressive aphasia (PPA) with Frontotemporal dementia pathology- semantic (svPPA) and non-fluent (nfvPPA) exhibit both shared and distinct features. The phenotypic heterogeneity stems from alterations in underlying brain networks. Investigating the common network (CN) and variant-specific unique network (UN) is critical to understanding the pathology of these conditions. Additionally, examining the evolution of these networks is key to elucidating disease progression. Method We applied algebraic-topology to explore the CN and UN using individualised resting-state fMRI data from 31 patients with nfvPPA, 32 with svPPA, and 38 age- and sex-matched controls (scanned at first visit). Using persistent homology, we identified the networks that differentiated ( p  < 0.01) each patient group from healthy controls. Since the subset of these subjects was scanned at the 6th and 12th months, the longitudinal changes in the rsfMRI networks were evaluated at each interval. Network features were correlated with clinical behaviours, and the longitudinal impact of the changes in these networks on behaviours was evaluated over the 12-month period. To validate the rsfMRI networks and the longitudinal changes, we evaluated the grey matter (GM) volume, GM atrophy and the rate-of-atrophy of the brain areas. To corroborate the findings, we applied persistent homology on the structural networks derived from diffusion tensor images. Result We found the existence of a left lateralised functional network identical in both PPA groups. This CN, comprising regions associated with language and cognition, remained stable over time (12 months period) and was associated with the severity of dementia. Conversely, the right-dominant UN in both variants showed progressive disintegration annually. In svPPA, cerebellar disassociation led to a decline in daily life activities, while parietal lobe degradation in nfvPPA impaired naming abilities. The CN and UN with similar regions were also found in the structural connectivity and the longitudinal changes in UN aligned with accelerated GM atrophy in the affected regions. Discussion Given the limited availability of pharmacological treatments, rehabilitation in PPA has primarily focused on modulating the left hemisphere using brain stimulation techniques. However, our findings indicate that while the disintegrated left hemispheric CN remained relatively stable, dysconnectivity progressed in the right hemisphere. These observations, along with the phylogenetic organization of brain networks and the variant-specific patterns of progression, highlight the need to incorporate right hemispheric rehabilitation strategies alongside the conventional left-hemispheric approaches in PPA.