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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., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Primary progressive aphasia (PPA) is comprised of three subtypes: logopenic (lvPPA), non-fluent (nfvPPA), and semantic (svPPA). We used magnetic resonance spectroscopy (MRS) to measure tissue-corrected metabolite levels in the left inferior frontal gyrus (IFG) and right sensorimotor cortex (SMC) from 61 PPA patients. We aimed to: (1) characterize subtype differences in metabolites; and (2) test for metabolite associations with symptom severity. tCr differed by subtype across the left IFG and right SMC. tCr levels were lowest in lvPPA and highest in svPPA. tCr levels predicted lvPPA versus svPPA diagnosis. Higher IFG tCr and lower Glx correlated with greater disease severity. As tCr is involved in brain energy metabolism, svPPA pathology might involve changes in specific cellular energy processes. Perturbations to cellular energy homeostasis in language areas may contribute to symptoms. Reduced cortical excitatory capacity (i.e. lower Glx) in language regions may also contribute to symptoms. Thus, tCr may be useful for differentiating between PPA subtypes, and both tCr and Glx might have utility in understanding PPA mechanisms and tracking progression., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Primary Progressive Aphasia (PPA) is a neurodegenerative disorder primarily affecting language functions. Neuromodulatory techniques (e.g., transcranial direct current stimulation, active-tDCS) and behavioral (speech-language) therapy have shown promising results in treating speech and language deficits in PPA patients. One mechanism of active-tDCS efficacy is through modulation of network functional connectivity (FC). It remains unknown how biological sex influences FC and active-tDCS or language treatment(s). In the current study, we compared sex differences, induced by active-tDCS and language therapy alone, in the default mode and language networks, acquired during resting-state fMRI in 36 PPA patients. Using a novel statistical method, the covariate-assisted-principal-regression (CAPs) technique, we found sex and age differences in FC changes following active-tDCS. In the default mode network (DMN): (1) men (in both conditions) showed greater FC in DMN than women. (2) men who received active-tDCS showed greater FC in the DMN than men who received language-treatment only. In the language network: (1) women who received active-tDCS showed significantly greater FC across the language network than women who received sham-tDCS. As age increases, regardless of sex and treatment condition, FC in language regions decreases. The current findings suggest active-tDCS treatment in PPA alters network-specific FC in a sex-dependent manner., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Stroke and neurodegenerative diseases differ along several dimensions, including their temporal trajectories -abrupt onset versus slow disease progression. Despite these differences, they can give rise to very similar cognitive impairments, such as specific forms of aphasia. What has been scarcely investigated, however, is the extent to which the underlying functional neuroplastic consequences are similar or different for these diseases. Here, for the first time, we directly compare changes in the brain's functional network connectivity, measured with resting-state fMRI, in stroke and progressive neurological disease. Specifically, we examined two groups of individuals with chronic post-stroke aphasia or non-fluent primary progressive aphasia, matched for their behavioral profiles and distribution of left-hemisphere damage. Using previous proposals regarding the neural functional connectivity (FC) phenotype of stroke as a starting point, we compared the two diseases in terms of homotopic FC, intra-hemispheric FC changes and also the symmetry of the FC patterns between the two hemispheres. We found, first, that progressive disease showed significantly higher levels of homotopic connectivity than neurotypical controls and, further, that stroke showed the reverse pattern. For both groups these effects were found to be behaviorally relevant. In addition, within the directly impacted left hemisphere, FC changes for the two diseases were significantly correlated. In contrast, in the right hemisphere, the FC changes differed markedly between the two groups, with the progressive disease group exhibiting rather symmetrical FC changes across the hemispheres whereas the post-stroke group showed asymmetrical FC changes across the hemispheres. These findings constitute novel evidence that the functional connectivity consequences of stroke and neurodegenerative disease can be very different despite similar behavioral outcomes and damage foci. Specifically, stroke may lead to greater independence of hemispheric responses, while neurodegenerative disease may produce more symmetrical changes across the hemispheres and more synchronized activity between the two hemispheres., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

In 1906, Pierre Marie triggered a heated controversy and an exchange of articles with Jules Déjerine over the localization of language functions in the human brain. The debate spread internationally. One of the timeliest responses, that appeared in print 1 month after Marie's paper, came from Christofredo Jakob, a Bavarian-born neuropathologist working in Buenos Aires. The present study comprises an English translation of Jakob's 1906 paper and a discussion of Jakob's ideas on the localizationist-holistic approach regarding the role of Broca's area. This issue is still at the core of scientific debate in the light of current neuropsychological and neuroimaging findings.

In 1906, the year of the renowned holistic-localizationist controversy between neurologists Pierre Marie and Jules Déjèrine in Paris, Christfried Jakob, a protagonist researcher of the cerebral cortex at the time working in Argentina, published two relevant articles entitled 'Does Broca's area exist?' and 'Anatomo-biological considerations on the centers of language'. The two articles addressed neuropsychological and developmental aspects of language functions in normality and pathology with regard to the brain areas that subserve them. The present article provides an English translation of Jakob's second paper, on the embryonic and postnatal development of brain areas related to language. The information given and the views expressed may still shed, a century later, useful light on our understanding of brain-language relationships.

In this paper we investigated the effects of configurational asymmetry in prefixed verbs in French. We used a simple lexical decision paradigm to compare prefixed verbs with external and internal prefixes as specified in linguistic theory (Di Sciullo, 1997) where external prefixes do not change the aktionsart and the verb argument structure of the verb, but internal prefixes do change the aktionsart and may change the verb argument structure of the verb. In Experiment 1 we tested the bi-valent prefix dé- where the configurational difference between external and internal properties of a prefix did not elicit differential response latencies. However, in Experiment 2, where unambiguous prefixes (internal en- and external ré-) were tested, the external prefix elicited longer latencies. These results are discussed with respect to the linguistic constraints the configurational properties of prefixes place upon psycholinguistic models of lexical access, as well as with respect to the effects of prefix bi-valence in the recognition of prefixed verbs.

The issue of regular-irregular past tense formation was examined in a cross-modal lexical decision task in Modern Greek, a language where the orthographic and phonological overlap between present and past tense stems is the same for both regular and irregular verbs. The experiment described here is a follow-up study of previous visual lexical decision experiments (Tsapkini, Kehayia, & Harema, 2002) that also addressed the regular-irregular distinction in Greek. In the present experiment, we investigated the effect of input modality in lexical processing and compared different types of regular and irregular verbs. In contrast to our previous intra-modal (visual-visual) priming experiments, in this cross-modal (auditory-visual) priming study, we found that regular verbs with an orthographically salient morphemic aspectual marker elicited the same facilitation as those without an orthographically salient marker. However, irregular verbs did not exhibit a different priming pattern with respect to modality. We interpret these results in the framework of a two-level lexical processing approach with modality-specific access representations at a surface level and modality-independent morphemic representations at a deeper level.

The present study investigates the relationship between morphological regularity and form during lexical processing using a visual priming paradigm varying the prime duration. We addressed the effect of regularity on morphological facilitation in nouns and verbs by exploiting particular characteristics of a highly inflected language, Greek, in which it is possible to manipulate morphological regularity while controlling the degree of orthographic overlap between morphological relatives. The effects of morphological regularity were found to crucially depend on the time course of lexical access. Moreover, morphological regularity was found to affect nouns and verbs differentially. We interpret these findings with respect to the distinction between affix processing and allomorph retrieval and discuss the issues of form overlap and orthographic boundaries in morphological processing.