High-Intensity Aphasia Therapy Is Cost-Effective in People With Poststroke Aphasia: Evidence From the COMPARE Trial.

BACKGROUND: Evidence from systematic reviews confirms that speech and language interventions for people with aphasia during the chronic phase after stroke (>6 months) improve word retrieval, functional communication, and communication-related quality of life. However, there is limited evidence of their cost-effectiveness. We aimed to estimate the cost per quality-adjusted life year gained from 2 speech and language therapies compared with usual care in people with aphasia during the chronic phase (median, 2.9 years) after stroke. METHODS: A 3-arm, randomized controlled trial compared constraint-induced aphasia therapy plus (CIAT-Plus) and multimodality aphasia therapy (M-MAT) with usual care in 216 people with chronic aphasia. Participants were administered a standardized questionnaire before intervention and at 12 weeks after the 2-week intervention/control period to ascertain health service utilization, employment changes, and informal caregiver burden. Unit prices from Australian sources were used to estimate costs in 2020. Quality-adjusted life years were estimated using responses to the EuroQol-5 Dimension-3 Level questionnaire. To test uncertainty around the differences in costs and outcomes between groups, bootstrapping was used with the cohorts resampled 1000 times. RESULTS: Overall 201/216 participants were included (mean age, 63 years, 29% moderate or severe aphasia, 61 usual care, 70 CIAT-Plus, 70 M-MAT). There were no statistically significant differences in mean total costs ($13 797 usual care, $17 478 CIAT-Plus, $11 113 M-MAT) and quality-adjusted life years (0.19 usual care, 0.20 CIAT-Plus, 0.20 M-MAT) between groups. In bootstrapped analysis of CIAT-Plus, 21.5% of iterations were likely to result in better outcomes and be cost saving (dominant) compared with usual care. In contrast, 72.4% of iterations were more favorable for M-MAT than usual care. CONCLUSIONS: We observed that both treatments, but especially M-MAT, may result in better outcomes at an acceptable additional cost, or potentially with cost savings. These findings are relevant in advocating for the use of these therapies for chronic aphasia after stroke.

High-Intensity Aphasia Intervention Is Minimally Fatiguing in Chronic Aphasia: An Analysis of Participant Self-Ratings From a Large Randomized Controlled Trial.

BACKGROUND: High-intensity therapy is recommended in current treatment guidelines for chronic poststroke aphasia. Yet, little is known about fatigue levels induced by treatment, which could interfere with rehabilitation outcomes. We analyzed fatigue experienced by people with chronic aphasia (>6 months) during high-dose interventions at 2 intensities. METHODS: A retrospective observational analysis was conducted on self-rated fatigue levels of people with chronic aphasia (N=173) collected during a previously published large randomized controlled trial of 2 treatments: constraint-induced aphasia therapy plus and multi-modality aphasia therapy. Interventions were administered at a higher intensity (30 hours over 2 weeks) or lower intensity (30 hours over 5 weeks). Participants rated their fatigue on an 11-point scale before and after each day of therapy. Data were analyzed using Bayesian ordinal multilevel models. Specifically, we considered changes in self-rated participant fatigue across a therapy day and over the intervention period. RESULTS: Data from 144 participants was analyzed. Participants were English speakers from Australia or New Zealand (mean age, 62 [range, 18-88] years) with 102 men and 42 women. Most had mild (n=115) or moderate (n=52) poststroke aphasia. Median ratings of the level of fatigue by people with aphasia were low (1 on a 0-10-point scale) at the beginning of the day. Ratings increased slightly (+1.0) each day after intervention, with marginally lower increases in the lower intensity schedule. There was no evidence of accumulating fatigue over the 2- or 5-week interventions. CONCLUSIONS: Findings suggest that intensive intervention was not associated with large increases in fatigue for people with chronic aphasia enrolled in the COMPARE trial (Constraint-Induced or Multimodality Personalised Aphasia Rehabilitation). Fatigue did not change across the course of the intervention. This study provides evidence that intensive treatment was minimally fatiguing for stroke survivors with chronic aphasia, suggesting that fatigue is not a barrier to high-intensity treatment.

Non-pharmacological interventions for improving language and communication in people with primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) accounts for approximately 43% of frontotemporal dementias and is mainly characterised by a progressive impairment of speech and communication abilities. Three clinical variants have been identified: (a) non-fluent/agrammatic, (b) semantic, and (c) logopenic/phonological PPA variants. There is currently no curative treatment for PPA, and the disease progresses inexorably over time, with devastating effects on speech and communication ability, functional status, and quality of life. Several non-pharmacological interventions that may improve symptoms (e.g. different forms of language training and non-invasive brain stimulation) have been investigated in people with PPA. OBJECTIVES: To assess the effects of non-pharmacological interventions for people with PPA on word retrieval (our primary outcome), global language functions, cognition, quality of life, and adverse events. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's trial register, MEDLINE (Ovid SP), Embase (Ovid SP), four other databases and two other trial registers. The latest searches were run on 26 January 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effects of non-pharmacological interventions in people with PPA. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: There were insufficient data available to conduct the network meta-analyses that we had originally planned (due to trial data being insufficiently reported or not reported at all, as well as the heterogeneous content of the included interventions). Therefore, we provide a descriptive summary of the included studies and results. We included 10 studies, with a total of 132 participants, evaluating non-pharmacological interventions. These were: transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) as stand-alone treatments (used by two and one studies, respectively); tDCS combined with semantic and phonological word-retrieval training (five studies); tDCS combined with semantic word-retrieval training (one study); and tDCS combined with phonological word-retrieval training (one study). Results for our primary outcome of word retrieval were mixed. For the two studies that investigated the effects of tDCS as stand-alone treatment compared to placebo ("sham") tDCS, we rated the results as having very low-certainty evidence. One study found a significant beneficial effect on word retrieval after active tDCS; one study did not report any significant effects in favour of the active tDCS group. Five studies investigated tDCS administered to the dorsolateral prefrontal cortex, inferior frontal cortex, left frontotemporal region, or the temporoparietal cortex, combined with semantic and phonological word-retrieval training. The most consistent finding was enhancement of word-retrieval ability for trained items immediately after the intervention, when behavioural training was combined with active tDCS compared to behavioural training plus sham tDCS. We found mixed effects for untrained items and maintenance of treatment effects during follow-up assessments. We rated the certainty of the evidence as very low in all studies. One study investigated tDCS combined with semantic word-retrieval training. Training was provided across 15 sessions with a frequency of three to five sessions per week, depending on the personal preferences of the participants. tDCS targeted the left frontotemporal region. The study included three participants: two received 1 mA stimulation and one received 2 mA stimulation. The study showed mixed results. We rated it as very low-certainty evidence. One study investigated tDCS combined with phonological word-retrieval training. Training was again provided across 15 sessions over a period of three weeks. tDCS targeted the left inferior frontal gyrus. This study showed a significantly more pronounced improvement for trained and untrained words in favour of the group that had received active tDCS, but we rated the certainty of the evidence as very low. One study compared active rTMS applied to an individually determined target site to active rTMS applied to a control site (vertex) for effects on participants' word retrieval. This study demonstrated better word retrieval for active rTMS administered to individually determined target brain regions than in the control intervention, but we rated the results as having a very low certainty of evidence. Four studies assessed overall language ability, three studies assessed cognition, five studies assessed potential adverse effects of brain stimulation, and one study investigated quality of life. AUTHORS' CONCLUSIONS: There is currently no high-certainty evidence to inform clinical decision-making regarding non-pharmacological treatment selection for people with PPA. Preliminary evidence suggests that the combination of active tDCS with specific language therapy may improve impaired word retrieval for specifically trained items beyond the effects of behavioural treatment alone. However, more research is needed, including high-quality RCTs with detailed descriptions of participants and methods, and consideration of outcomes such as quality of life, depressive symptoms, and overall cognitive functioning. Moreover, studies assessing optimal treatments (i.e. behavioural interventions, brain stimulation interventions, and their combinations) for individual patients and PPA subtypes are needed. We were not able to conduct the planned (network) meta-analyses due to missing data that could not be obtained from most of the authors, a general lack of RCTs in the field, and heterogeneous interventions in eligible trials. Journals should implement a mandatory data-sharing requirement to assure transparency and accessibility of data from clinical trials.

[Transcranial direct current stimulation to enhance training effectiveness in chronic poststroke aphasia-A challenge for recruiting participants]. / Transkranielle Gleichstromstimulation zur Verbesserung der Trainingseffektivität bei chronischer Aphasie nach Schlaganfall ­ wie gelingt die Studienrekrutierung Betroffener?

INTRODUCTION/BACKGROUND: DC_TRAIN_APHASIA is an ongoing multicenter, randomized controlled trial, conducted since November 2019 under the lead of the University Medicine Greifswald (ClinicalTrials.gov Identifier: NCT03930121). The study seeks to determine whether adjuvant transcranial direct current stimulation (tDCS) can increase the effectiveness of a 3­week treatment with intensive speech-language therapy in chronic post-stroke aphasia. MATERIAL AND METHOD: Until the end of 2024, a total of 130 patients are to be included in Germany. Recruitment has been a challenge throughout the study and substantial efforts went into devising innovative recruiting approaches. Standard recruitment strategies were used, such as directly approaching people with aphasia in clinical settings, inpatient and outpatient language rehabilitation facilities, and patient support and advocacy groups, alongside more innovative techniques including radio commercials, dissemination of study information via national television and social media platforms. PROVISIONAL RESULTS: Up until now, 110 patients have been included into the study. The largest short-term response was achieved via television and radio. The largest long-term response was obtained through recruitment via logopaedic and neurological facilities, patient support groups, and social media. Participants served as "testimonials", expressing that they were satisfied with the therapy and the tDCS application. DISCUSSION: The multicenter study DC_TRAIN_APHASIA aims to provide evidence on tDCS as an adjuvant application to increase the effect size of intensive speech-language therapy in chronic post-stroke aphasia. The present review may guide future studies in recruiting samples that involve people with impaired communicative abilities.

Right hemispheric structural connectivity and poststroke language recovery.

Poststroke aphasia typically results from brain damage to the left-lateralized language network. The contribution of the right-lateralized homologues in aphasia recovery remains equivocal. In this longitudinal observational study, we specifically investigated the role of right hemisphere structural connectome in aphasia recovery. Twenty-two patients with aphasia after a left hemispheric stroke underwent comprehensive language assessment at the early subacute and chronic stages. A novel structural connectometry approach, using multi-shell diffusion-weighted MRI data collected at the early subacute stage, was used to evaluate the relationship between right hemisphere white matter connectome and language production and comprehension abilities at early subacute stage. Moreover, we evaluated the relationship between early subacute right hemisphere white matter connectome and longitudinal change in language production and comprehension abilities. All results were corrected for multiple comparisons. Connectometry analyses revealed negative associations between early subacute stage right hemisphere structural connectivity and language production, both cross-sectionally and longitudinally (pFDR < .0125). In turn, only positive associations between right hemisphere structural connectivity and language comprehension were observed, both cross-sectionally and longitudinally (pFDR < .0125). Interhemispheric connectivity was highly associated with comprehension scores. Our results shed light on the discordant interpretations of previous findings, by providing evidence that while some right hemisphere white matter pathways may make a maladaptive contribution to the recovery of language, other pathways support the recovery of language, especially comprehension abilities.

Results of the COMPARE trial of Constraint-induced or Multimodality Aphasia Therapy compared with usual care in chronic post-stroke aphasia.

BACKGROUND: While meta-analyses confirm treatment for chronic post-stroke aphasia is effective, a lack of comparative evidence for different interventions limits prescription accuracy. We investigated whether Constraint-Induced Aphasia Therapy Plus (CIAT-plus) and/or Multimodality Aphasia Therapy (M-MAT) provided greater therapeutic benefit compared with usual community care and were differentially effective according to baseline aphasia severity. METHODS: We conducted a three-arm, multicentre, parallel group, open-label, blinded endpoint, phase III, randomised-controlled trial. We stratified eligible participants by baseline aphasia on the Western Aphasia Battery-Revised Aphasia Quotient (WAB-R-AQ). Groups of three participants were randomly assigned (1:1:1) to 30 hours of CIAT-Plus or M-MAT or to usual care (UC). Primary outcome was change in aphasia severity (WAB-R-AQ) from baseline to therapy completion analysed in the intention-to-treat population. Secondary outcomes included word retrieval, connected speech, functional communication, multimodal communication, quality of life and costs. RESULTS: We analysed 201 participants (70 in CIAT-Plus, 70 in M-MAT and 61 in UC). Aphasia severity was not significantly different between groups at postintervention: 1.05 points (95% CI -0.78 to 2.88; p=0.36) UC group vs CIAT-Plus; 1.06 points (95% CI -0.78 to 2.89; p=0.36) UC group vs M-MAT; 0.004 points (95% CI -1.76 to 1.77; p=1.00) CIAT-Plus vs M-MAT. Word retrieval, functional communication and communication-related quality of life were significantly improved following CIAT-Plus and M-MAT. Word retrieval benefits were maintained at 12-week follow-up. CONCLUSIONS: CIAT-Plus and M-MAT were effective for word retrieval, functional communication, and quality of life, while UC was not. Future studies should explore predictive characteristics of responders and impacts of maintenance doses. TRIAL REGISTRATION NUMBER: ACTRN 2615000618550.

The Right Temporoparietal Junction Is Causally Associated with Embodied Perspective-taking.

A prominent theory claims that the right temporoparietal junction (rTPJ) is especially associated with embodied processes relevant to perspective-taking. In the present study, we use high-definition transcranial direct current stimulation to provide evidence that the rTPJ is causally associated with the embodied processes underpinning perspective-taking. Eighty-eight young human adults were stratified to receive either rTPJ or dorsomedial PFC anodal high-definition transcranial direct current stimulation in a sham-controlled, double-blind, repeated-measures design. Perspective-tracking (line-of-sight) and perspective-taking (embodied rotation) were assessed using a visuo-spatial perspective-taking task that required understanding what another person could see or how they see it, respectively. Embodied processing was manipulated by positioning the participant in a manner congruent or incongruent with the orientation of an avatar on the screen. As perspective-taking, but not perspective-tracking, is influenced by bodily position, this allows the investigation of the specific causal role for the rTPJ in embodied processing. Crucially, anodal stimulation to the rTPJ increased the effect of bodily position during perspective-taking, whereas no such effects were identified during perspective-tracking, thereby providing evidence for a causal role for the rTPJ in the embodied component of perspective-taking. Stimulation to the dorsomedial PFC had no effect on perspective-tracking or taking. Therefore, the present study provides support for theories postulating that the rTPJ is causally involved in embodied cognitive processing relevant to social functioning.SIGNIFICANCE STATEMENT The ability to understand another's perspective is a fundamental component of social functioning. Adopting another perspective is thought to involve both embodied and nonembodied processes. The present study used high-definition transcranial direct current stimulation (HD-tDCS) and provided causal evidence that the right temporoparietal junction is involved specifically in the embodied component of perspective-taking. Specifically, HD-tDCS to the right temporoparietal junction, but not another hub of the social brain (dorsomedial PFC), increased the effect of body position during perspective-taking, but not tracking. This is the first causal evidence that HD-tDCS can modulate social embodied processing in a site-specific and task-specific manner.

The Shape of Things to Come in Speech Production: A Functional Magnetic Resonance Imaging Study of Visual Form Interference during Lexical Access.

Studies of context effects in speech production have shown that semantic feature overlap produces interference in naming of categorically related objects. In neuroimaging studies, this semantic interference effect is consistently associated with involvement of left superior and middle temporal gyri. However, at least part of this effect has recently been shown to be attributable to visual form similarity, as categorically related objects typically share visual features. This fMRI study examined interference produced by visual form overlap in the absence of a category relation in a picture-word interference paradigm. Both visually similar and visually dissimilar distractors led to increased BOLD responses in the left inferior frontal gyrus compared with the congruent condition. Naming pictures in context with a distractor word denoting an object visually similar in form slowed RTs compared with unrelated words and was associated with reduced activity in the left posterior middle temporal gyrus. This area is reliably observed in lexical level processing during language production tasks. No significant differential activity was observed in areas typically engaged by early perceptual or conceptual feature level processing or in areas proposed to be engaged by postlexical language processes, suggesting that visual form interference does not arise from uncertainty or confusion during perceptual or conceptual identification or after lexical processing. We conclude that visual form interference has a lexical locus, consistent with the predictions of competitive lexical selection models.

Neuroplasticity and aphasia treatments: new approaches for an old problem.

Given the profound impact of language impairment after stroke (aphasia), neuroplasticity research is garnering considerable attention as means for eventually improving aphasia treatments and how they are delivered. Functional and structural neuroimaging studies indicate that aphasia treatments can recruit both residual and new neural mechanisms to improve language function and that neuroimaging modalities may hold promise in predicting treatment outcome. In relatively small clinical trials, both non-invasive brain stimulation and behavioural manipulations targeting activation or suppression of specific cortices can improve aphasia treatment outcomes. Recent language interventions that employ principles consistent with inducing neuroplasticity also are showing improved performance for both trained and novel items and contexts. While knowledge is rapidly accumulating, larger trials emphasising how to select optimal paradigms for individualised aphasia treatment are needed. Finally, a model of how to incorporate the growing knowledge into clinical practice could help to focus future research.

Age-dependent effects of brain stimulation on network centrality.

Functional magnetic resonance imaging (fMRI) studies have suggested that advanced age may mediate the effects of transcranial direct current stimulation (tDCS) on brain function. However, studies directly comparing neural tDCS effects between young and older adults are scarce and limited to task-related imaging paradigms. Resting-state (rs-) fMRI, that is independent of age-related differences in performance, is well suited to investigate age-associated differential neural tDCS effects. Three "online" tDCS conditions (anodal, cathodal, sham) were compared in a cross-over, within-subject design, in 30 young and 30 older adults. Active stimulation targeted the left sensorimotor network (active electrode over left sensorimotor cortex with right supraorbital reference electrode). A graph-based rs-fMRI data analysis approach (eigenvector centrality mapping) and complementary seed-based analyses characterized neural tDCS effects. An interaction between anodal tDCS and age group was observed. Specifically, centrality in bilateral paracentral and posterior regions (precuneus, superior parietal cortex) was increased in young, but decreased in older adults. Seed-based analyses revealed that these opposing patterns of tDCS-induced centrality modulation originated from differential effects of tDCS on functional coupling of the stimulated left paracentral lobule. Cathodal tDCS did not show significant effects. Our study provides first evidence for differential tDCS effects on neural network organization in young and older adults. Anodal stimulation mainly affected coupling of sensorimotor with ventromedial prefrontal areas in young and decoupling with posteromedial areas in older adults.

Stimulation of Dorsolateral Prefrontal Cortex Enhances Adaptive Cognitive Control: A High-Definition Transcranial Direct Current Stimulation Study.

Conflict adaptation is a hallmark effect of adaptive cognitive control and refers to the adjustment of control to the level of previously experienced conflict. Conflict monitoring theory assumes that the dorsolateral prefrontal cortex (DLPFC) is causally involved in this adjustment. However, to date, evidence in humans is predominantly correlational, and heterogeneous with respect to the lateralization of control in the DLPFC. We used high-definition transcranial direct current stimulation (HD-tDCS), which allows for more focal current delivery than conventional tDCS, to clarify the causal involvement of the DLPFC in conflict adaptation. Specifically, we investigated the regional specificity and lateralization of potential beneficial stimulation effects on conflict adaptation during a visual flanker task. One hundred twenty healthy participants were assigned to four HD-tDCS conditions: left or right DLPFC or left or right primary motor cortex (M1). Each group underwent both active and sham HD-tDCS in crossover, double-blind designs. We obtained a sizeable conflict adaptation effect (measured as the modulation of the flanker effect as a function of previous response conflict) in all groups and conditions. However, this effect was larger under active HD-tDCS than under sham stimulation in both DLPFC groups. In contrast, active stimulation had no effect on conflict adaptation in the M1 groups. In sum, the present results indicate that the DLPFC plays a causal role in adaptive cognitive control, but that the involvement of DLPFC in control is not restricted to the left or right hemisphere. Moreover, our study confirms the potential of HD-tDCS to modulate cognition in a regionally specific manner. SIGNIFICANCE STATEMENT: Conflict adaptation is a hallmark effect of adaptive cognitive control. While animal studies have suggested causal involvement of the DLPFC in this phenomenon, such evidence is currently lacking in humans. The present study used high-definition transcranial direct current stimulation (HD-tDCS) to demonstrate that the DLPFC is causally involved in conflict adaptation in humans. Our study confirms a central claim of conflict monitoring theory, which up to now has predominantly relied on correlational studies. Our results further indicate an equal involvement of the left and right DLPFC in adaptive control, whereas stimulation of a control region-the primary motor cortex-had no effect on adaptive control. The study thus confirms the potential of HD-tDCS to modulate cognition in a regionally specific manner.

Effects of Transcranial Direct Current Stimulation on Neural Networks in Young and Older Adults

Transcranial direct current stimulation (tDCS) may be a viable tool to improve motor and cognitive function in advanced age. However, although a number of studies have demonstrated improved cognitive performance in older adults, other studies have failed to show restorative effects. The neural effects of beneficial stimulation response in both age groups is lacking. In the current study, tDCS was administered during simultaneous fMRI in 42 healthy young and older participants. Semantic word generation and motor speech baseline tasks were used to investigate behavioral and neural effects of uni- and bihemispheric motor cortex tDCS in a three-way, crossover, sham tDCS controlled design. Independent components analysis assessed differences in task-related activity between the two age groups and tDCS effects at the network level. We also explored whether laterality of language network organization was effected by tDCS. Behaviorally, both active tDCS conditions significantly improved semantic word retrieval performance in young and older adults and were comparable between groups and stimulation conditions. Network-level tDCS effects were identified in the ventral and dorsal anterior cingulate networks in the combined sample during semantic fluency and motor speech tasks. In addition, a shift toward enhanced left laterality was identified in the older adults for both active stimulation conditions. Thus, tDCS results in common network-level modulations and behavioral improvements for both age groups, with an additional effect of increasing left laterality in older adults.

Transcranial direct current stimulation effects on neural processing in post-stroke aphasia.

Non-invasive transcranial direct current stimulation (tDCS) can enhance recovery after stroke. However, fundamental knowledge about how tDCS impacts neural processing in the lesioned human brain is currently lacking. In the present study, it was investigated how tDCS modulates brain function in patients with post-stroke language impairment (aphasia). In a cross-over, randomized trial, patients named pictures of common objects during functional magnetic resonance imaging (fMRI). Concurrently, excitatory (anodal-) or sham-tDCS (1 mA, 20 min, or 30 s, respectively) was administered to the left primary motor cortex, a montage with demonstrated potential to improve aphasic language. By choosing stimuli that could reliable be named by the patients, the authors aimed to derive a pure measure of stimulation effects that was independent of treatment or performance effects and to assess how tDCS interacts with the patients' residual language network. Univariate fMRI data analysis revealed reduced activity in domain-general regions mediating high-level cognitive control during anodal-tDCS. Independent component functional network analysis demonstrated selectively increased language network activity and an inter-correlated shift from higher to lower frequency bands, indicative of increased within-network communication. Compared with healthy controls, anodal-tDCS resulted in overall "normalization" of brain function in the patients. These results demonstrate for the first time how tDCS modulates neural processing in stroke patients. Such information is crucial to assure that behavioral treatments targeting specific neural circuits overlap with regions that are modulated by tDCS, thereby maximizing stimulation effects during therapy. Hum Brain Mapp 38:1518-1531, 2017. © 2016 Wiley Periodicals, Inc.

Electrical stimulation of the motor cortex enhances treatment outcome in post-stroke aphasia.

Transcranial direct current stimulation has shown promise to improve recovery in patients with post-stroke aphasia, but previous studies have only assessed stimulation effects on impairment parameters, and evidence for long-term maintenance of transcranial direct current stimulation effects from randomized, controlled trials is lacking. Moreover, due to the variability of lesions and functional language network reorganization after stroke, recent studies have used advanced functional imaging or current modelling to determine optimal stimulation sites in individual patients. However, such approaches are expensive, time consuming and may not be feasible outside of specialized research centres, which complicates incorporation of transcranial direct current stimulation in day-to-day clinical practice. Stimulation of an ancillary system that is functionally connected to the residual language network, namely the primary motor system, would be more easily applicable, but effectiveness of such an approach has not been explored systematically. We conducted a randomized, parallel group, sham-controlled, double-blind clinical trial and 26 patients with chronic aphasia received a highly intensive naming therapy over 2 weeks (8 days, 2 × 1.5 h/day). Concurrently, anodal-transcranial direct current stimulation was administered to the left primary motor cortex twice daily at the beginning of each training session. Naming ability for trained items (n = 60 pictures that could not be named during repeated baseline assessments), transfer to untrained items (n = 284 pictures) and generalization to everyday communication were assessed immediately post-intervention and 6 months later. Naming ability for trained items was significantly improved immediately after the end of the intervention in both the anodal (Cohen's d = 3.67) and sham-transcranial direct current stimulation groups (d = 2.10), with a trend for larger gains in the anodal-transcranial direct current stimulation group (d = 0.71). Treatment effects for trained items were significantly better maintained in the anodal-transcranial direct current stimulation group 6 months later (d = 1.19). Transfer to untrained items was significantly larger in the anodal-transcranial direct current stimulation group after the training (d = 1.49) and during the 6 month follow-up assessment (d = 3.12). Transfer effects were only maintained in the anodal-transcranial direct current stimulation group. Functional communication was significantly more improved in the anodal-transcranial direct current stimulation group at both time points compared to patients treated with sham-transcranial direct current stimulation (d = 0.75-0.99). Our results provide the first evidence from a randomized, controlled trial that transcranial direct current stimulation can improve both function and activity-related outcomes in chronic aphasia, with medium to large effect sizes, and that these effects are maintained over extended periods of time. These effects were achieved with an easy-to-implement and thus clinically feasible motor-cortex montage that may represent a promising 'backdoor' approach to improve language recovery after stroke.

Transcranial direct current stimulation in mild cognitive impairment: Behavioral effects and neural mechanisms.

INTRODUCTION: The long preclinical phase of Alzheimer's disease provides opportunities for potential disease-modifying interventions in prodromal stages such as mild cognitive impairment (MCI). Anodal transcranial direct current stimulation (anodal-tDCS), with its potential to enhance neuroplasticity, may allow improving cognition in MCI. METHODS: In a double-blind, cross-over, sham-controlled study, anodal-tDCS was administered to the left inferior frontal cortex during task-related and resting-state functional magnetic resonance imaging (fMRI) to assess its impact on cognition and brain functions in MCI. RESULTS: During sham stimulation, MCI patients produced fewer correct semantic-word-retrieval responses than matched healthy controls, which was associated with hyperactivity in bilateral prefrontal regions. Anodal-tDCS significantly improved performance to the level of controls, reduced task-related prefrontal hyperactivity and resulted in "normalization" of abnormal network configuration during resting-state fMRI. DISCUSSION: Anodal-tDCS exerts beneficial effects on cognition and brain functions in MCI, thereby providing a framework to test whether repeated stimulation sessions may yield sustained reversal of cognitive deficits.

Anodal transcranial direct current stimulation temporarily reverses age-associated cognitive decline and functional brain activity changes.

The rising proportion of elderly people worldwide will yield an increased incidence of age-associated cognitive impairments, imposing major burdens on societies. Consequently, growing interest emerged to evaluate new strategies to delay or counteract cognitive decline in aging. Here, we assessed immediate effects of anodal transcranial direct current stimulation (atDCS) on cognition and previously described detrimental changes in brain activity attributable to aging. Twenty healthy elderly adults were assessed in a crossover sham-controlled design using functional magnetic resonance imaging (fMRI) and concurrent transcranial DCS administered to the left inferior frontal gyrus. Effects on performance and task-related brain activity were evaluated during overt semantic word generation, a task that is negatively affected by advanced age. Task-absent resting-state fMRI (RS-fMRI) assessed atDCS-induced changes at the network level independent of performance. Twenty matched younger adults served as controls. During sham stimulation, task-related fMRI demonstrated that enhanced bilateral prefrontal activity in older adults was associated with reduced performance. RS-fMRI revealed enhanced anterior and reduced posterior functional brain connectivity. atDCS significantly improved performance in older adults up to the level of younger controls; significantly reduced task-related hyperactivity in bilateral prefrontal cortices, the anterior cingulate gyrus, and the precuneus; and induced a more "youth-like" connectivity pattern during RS-fMRI. Our results provide converging evidence from behavioral analysis and two independent functional imaging paradigms that a single session of atDCS can temporarily reverse nonbeneficial effects of aging on cognition and brain activity and connectivity. These findings may translate into novel treatments to ameliorate cognitive decline in normal aging in the future.

Differential effects of dual and unihemispheric motor cortex stimulation in older adults.

Bihemispheric transcranial direct current stimulation (tDCS) is thought to upregulate excitability of the primary motor cortex (M1) using anodal stimulation while concurrently downregulating contralateral M1 using cathodal stimulation. This "dual" tDCS method enhances motor learning in healthy subjects and facilitates motor recovery after stroke. However, its impact on motor system activity and connectivity remains unknown. Therefore, we assessed neural correlates of dual and unihemispheric anodal tDCS effects in 20 healthy older subjects in a randomized, sham-controlled study using a cross-over design. Participants underwent tDCS and simultaneous functional magnetic resonance imaging during a choice reaction time task and at rest. Diffusion tensor imaging (DTI) allowed us to relate potential functional changes to structural parameters. The resting-state analysis demonstrated that, compared with sham, both dual and anodal tDCS decreased connectivity of right hippocampus and M1 (contralateral to the anode position) while increasing connectivity in the left prefrontal cortex. Notably, dual but not anodal tDCS enhanced connectivity of the left dorsal posterior cingulate cortex. Furthermore, dual tDCS yielded stronger activations in bilateral M1 compared with anodal tDCS when participants used either their left or right hand during the motor task. The corresponding tDCS-induced changes in laterality of activations were related to the microstructural status of transcallosal motor fibers. In conclusion, our results suggest that the impact of bihemispheric tDCS cannot be explained by mere add-on effects of anodal and concurrent cathodal stimulation, but rather by complex network modulations involving interhemispheric interactions and areas associated with motor control in the dorsal posterior cingulate cortex.

A systematic review and meta-analysis of socio-cognitive impairments in multiple sclerosis.

Socio-cognitive impairment is frequent in multiple sclerosis (MS). However, little is known about the relationship between other potentially relevant clinical symptoms (i.e., cognition, depression, fatigue) and the degree of socio-cognitive impairment, and neural mechanisms underlying socio-cognitive deficits in MS. Therefore, we meta-analytically quantified socio-cognitive impairment in MS. A systematic literature search in MEDLINE Ovid, Web of Science Core Collection, CENTRAL, and PsycInfo was conducted until December 2022. Studies investigating affective or cognitive theory of mind (a/cToM), visual perspective taking (VPT) and social decision making (SDM) in MS patients relative to healthy controls were included. Risk-of-bias (RoB) was assessed using the CLARITY group "Tool for Assessing RoB in Cohort Studies". Mediation analysis investigated the contribution of clinical symptoms to socio-cognitive impairment. In total, n = 8534 studies were screened, 58 were included in the systematic review, 27 in the meta-analyses. Most studies were rated with a moderate RoB. Meta-analyses confirmed impairment of both aToM and cToM in MS patients, with larger effect sizes for aToM. Mediation analysis demonstrated that higher levels of fatigue selectively predicted the degree of cToM impairment. There was insufficient data available to quantify impairment in other socio-cognitive domains. Fourteen structural and functional imaging studies were identified and characterized by substantial heterogeneity. Summarized, this study confirmed substantial socio-cognitive impairment in MS and highlights the potential exacerbating role of comorbid clinical symptoms. We identify several evidence gaps that need to be addressed in future large-scale studies using comprehensive and coordinated assessments of socio-cognitive parameters, potential mediators, and neural correlates.Trial registration: The pre-registered review protocol can be assessed at www.crd.york.ac.uk/PROSPERO/ (ID: CRD42020206225).

Improving mentalizing deficits in older age with region-specific transcranial direct current stimulation.

Older adults have difficulties to detect the intentions, thoughts, and feelings of others, indicating an age-associated decline of socio-cognitive abilities that are known as "mentalizing". These deficits in mental state recognition are driven by neurofunctional alterations in brain regions that are implicated in mentalizing, such as the right temporo-parietal junction (rTPJ) and the dorso-medial prefrontal cortex (dmPFC). We tested whether focal transcranial current stimulation (tDCS) of the rTPJ and dmPFC has the potential to eliminate mentalizing deficits in older adults. Mentalizing deficits were assessed with a novel mindreading task that required the recognition of mental states in child faces. Older adults (n = 60) performed worse than younger adults (n = 30) on the mindreading task, indicating age-dependent deficits in mental state recognition. These mentalizing deficits were ameliorated in older adults who received sham-controlled andodal tDCS over the rTPJ (n = 30) but remained unchanged in older adults who received sham-controlled andodal tDCS over the dmPFC (n = 30). We, thus, showed for the first time that anodal tDCS over the rTPJ has the potential to remediate age-dependent mentalizing deficits in a region-specific way. This provides a rationale for exploring stimulation-based interventions targeting mentalizing deficits in older age.

The role of frontal cortex in novel-word learning and consolidation: Evidence from focal transcranial direct current stimulation.

Previous studies have demonstrated that conventional transcranial direct current stimulation (tDCS) can enhance novel-word learning. However, because of the widespread current that is induced by these setups and lack of appropriate control conditions, little is known about the underlying neural mechanisms. In the present double-blinded and sham-tDCS controlled study, we investigated for the first time if regionally precise focal tDCS targeting two key nodes of the novel-word learning network at different time points would result in regionally and temporally distinct effects. 156 participants completed a contextual novel-word-learning paradigm and learning success was probed immediately after the acquisition period and 30-min later. Participants were randomly assigned to six stimulation conditions: Active tDCS (1.5 mA) was administered to left inferior frontal (IFG) or middle temporal gyrus (MTG), either during acquisition or delayed recall. Control groups received sham-tDCS either during acquisition or delayed recall (50% IFG/MTG). Data were analyzed with a generalized linear mixed model with a binomial link function in a Bayesian framework. Our results showed that frontal tDCS selectively increased accuracy gains from immediate to delayed recall, irrespective of timing of the stimulation. There was no evidence for beneficial effects of middle temporal gyrus tDCS. Our findings confirm that IFG tDCS can enhance novel-word learning in a regionally, but not timing specific way. Tentatively, this may be explained by enhancement of semantic selection processes resulting in more effective consolidation and/or retrieval. Future studies using longer time intervals between assessments are required to clarify the potential contribution of neurophysiological after-effects of IFG tDCS administered during acquisition to enhanced consolidation.