stroke aphasia case study

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Making Life Accessible to Oklahomans of All Ages and Abilities

Speech Communication Community Living Case Study:  Person with a Stroke

Person with a stroke just discharged from hospital to home..

This person has just had a stroke and has Aphasia. He no longer has clear, fluent speech and then sometimes says single words that do not make sense in the conversation. He no longer has good use of the right side of his body and needs a wheelchair. He is spending the majority of his time at home unless he is heading to doctor or therapy appointments.

Possible Recommendations:

This gentleman may need a device that is lightweight, so it can easily be carried in one hand. Another option would be to have the device mounted to his wheelchair, so that he does not have to carry it in his one good hand. Research shows that people who have had strokes benefit from communication tools organized using visual scene displays. This is when messages are displayed in the context of a scene – typically using real photos and programming “hot spots” with the messages. Another consideration is that when a communication option is selected, this person may want a complete sentence (or sentences) to be said out loud (versus single alphabet letters, single words, or short phrases).

Goals and Outcomes:

An important goal will be for this person to be able to independently communicate what he needs and wants accurately and in a timely way. He may need to call for help when he is alone in a room. He will also need to communicate with his doctors and therapists about aches, pains, and other needs.

See the attached HAAT Model form to see how to match the individual to needed AT.

Case Study Form – HAAT Model

• Case Study #3 – Word document

Sample solutions:

If you are interested in these recommended devices, please visit our  Device Loan Program  webpage to apply for a short-term loan.

• Open access
• Published: 26 August 2024

Deep vein thrombosis in patients with stroke or transient ischemic attack presenting with patent foramen ovale: a retrospective observational study

• Charlotte Huber 1 ,
• Stephan Stöbe 2 ,
• Andreas Hagendorff 2 ,
• Katja Sibylle Mühlberg 3 ,
• Karl-Titus Hoffmann 4 ,
• Berend Isermann 5 ,
• Rolf Wachter 2 ,
• Nikolaus von Dercks 6 ,
• Richard Schmidt 1 ,
• Johann Otto Pelz 1 &
• Dominik Michalski 1  

BMC Neurology volume  24 , Article number:  295 ( 2024 ) Cite this article

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Metrics details

Deep vein thrombosis (DVT) is discussed as a source of embolism for cerebral ischemia in the presence of patent foramen ovale (PFO). However, previous studies reported varying rates of DVT in stroke patients, and recommendations for screening are lacking. This study aimed to characterize patients with stroke or transient ischemic attack (TIA) and concomitant PFO and explore the rate of DVT and associated parameters.

Medical records were screened for patients with stroke or TIA and echocardiographic evidence of PFO. Concomitant DVT was identified according to compression ultrasonography of the lower limbs. A variety of demographic, clinical, and laboratory parameters, the RoPE and Wells scores were compared between patients with and without DVT.

Three-hundred-thirty-nine patients (mean age 61.2 ± 15.4 years, 61.1% male) with stroke or TIA and PFO, treated between 01/2015 and 12/2020, were identified. Stroke and TIA patients did not differ for demographic and vascular risk factors. DVT was found in 17 cases out of 217 (7.8%) with compression ultrasonography. DVT was associated with a history of DVT, cancer, previous immobilization, calf compression pain, calf circumference difference, and a few laboratory abnormalities, e.g., increased D-dimer. A multivariate regression model with stepwise backward selection identified the Wells score (odds ratio 35.46, 95%-confidence interval 4.71–519.92) as a significant predictor for DVT.

DVT is present in a relevant proportion of patients with cerebral ischemia and PFO, which needs to be considered for the individual diagnostic workup. The Wells score seems suitable for guiding additional examinations, i.e., compression ultrasonography.

Peer Review reports

Introduction

Autoptic studies have indicated patent foramen ovale (PFO) in about 25% of the general population [ 1 ]. Among patients with ischemic stroke considered as a cryptogenic event, the probability of presenting a PFO was found to be three times higher as compared to different controls [ 1 , 2 ]. Randomized controlled trials have investigated the closure of high-risk PFO in stroke patients and observed a decreased rate of recurrent events compared to medical treatment alone, which included different drugs affecting the coagulation system [ 3 , 4 , 5 ]. This led to the recommendation to consider PFO closure in selected stroke patients, including those with an age < 60 years, a high-risk PFO, and a lack of concurrent etiologic factors [ 6 , 7 , 8 ].

Despite the progress in handling stroke patients with cryptogenic stroke and coincident PFO, the underlying mechanism of PFO-associated stroke is still a matter of debate, and thus the individual diagnostic workup is rather challenging. A more recent perspective considers the PFO channel itself as the source of embolic events, while the traditional concept of paradoxical embolism comprised a deep vein thrombosis (DVT) as source of an embolus passing from the venous to the arterial system through the PFO [ 9 , 10 ]. The concept of stroke due to paradoxical embolism was first described in 1877 [ 11 ], followed by a few case reports [ 12 ]. Remarkably, earlier studies yielded highly varying rates of DVT in stroke patients with PFO, ranging from 7 to 27% [ 13 ]. As the presence of a DVT was not an inclusion criterion of the randomized controlled trials showing beneficial effects of PFO closure [ 3 , 4 , 5 ], the discussion regarding causal relationships is still ongoing. Further, these trials excluded patients presenting with transient-ischemic attack (TIA), even though this group is at considerable risk for secondary events [ 14 ], which may be even higher in the presence of a PFO.

On the individual level, knowledge of a DVT in the setting of stroke and the presence of PFO seems to be important: First, to determine individual stroke etiology as best as possible, which is essential for secondary prevention, and second, to identify conditions that entail, at least for a certain period, an anticoagulation independent of the cerebral event. For reliable detection of DVT, ultrasonography has proven beneficial in neurological diseases [ 15 ], but its time-consuming aspect and a limited availability might inhibit systematic screenings. So far, there is no clear recommendation for the diagnostic workup for stroke patients presenting with a PFO, especially regarding a potential DVT [ 6 , 16 ]. Uncertainties further exist regarding specific groups of patients, particularly those with TIA and an age older than 60 [ 10 ].

Therefore, this study aimed to characterize patients with stroke or TIA and concomitant PFO and explore the rate of DVT and associated parameters, which might help to guide the individualized diagnostic workup, particularly regarding additional examinations, i.e., ultrasonography.

Study design

For this retrospective, non-interventional study, hospital-based medical records of all stroke and TIA patients treated at the Department of Neurology of the University of Leipzig between January 2015 and December 2020 were screened for the International Statistical Classification of Diseases and Related Health Problems (ICD)-10 code I63.* (ischemic stroke) or G45.* (TIA) in conjunction with Q21.1 (PFO). Data obtained during the hospital stay were extracted from the electronic data storage systems.

The study was approved by the ethics committee of the Medical Faculty at the University of Leipzig (reference number 269/21-ek/) and performed in compliance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Further, the study was registered in “Deutsches Register klinischer Studien” (DRKS, reference number DRKS00025998). This study is reported according to STROBE guidelines [ 17 ].

Patients, evaluation of PFO and DVT

Patients were included if they had an age of at least 18 years, a stroke or TIA, and evidence of PFO. According to current conventions, stroke was defined as focal neurological symptom presenting for more than 24 h or evidence of an ischemic lesion on cerebral imaging [i.e., magnetic resonance imaging (MRI) or computed tomography (CT)], while TIA was defined as a transient focal neurological symptom without evidence of infarction on cerebral imaging [ 18 ]. For TIA, at least one of the following symptoms had to be presented: aphasia, dysarthria, facial paresis, sensory or motor impairment of at least one extremity. Cases with uncertain TIA as for example possible peripheral-vestibular disorders (e.g., transient dizziness), migraine, and psychological disorders were excluded.

The presence of a PFO was evaluated by transthoracic and transesophageal echocardiography during routine examination, performed by a cardiologist and documented in medical records. In cases of uncertainty, the original echocardiographic images were re-evaluated by a cardiologist. Echocardiographic examinations were performed by Vivid 7, Vivid E9, or Vivid E95 ultrasound system with a M5-S or a 4Vc phased array probe (GE Healthcare Ultrasound Germany, Solingen/München, Germany), usually including the application of a contrast agent (Gelafusal 4%, Serumwerk Bernburg AG, Bernburg, Germany). Cases presenting pathologies not following the strict definition of a PFO, i.e., atrial septal defects (ASD) II, were excluded.

Regarding DVT, information was also taken from medical records describing the findings of a compression ultrasonography of the lower limbs, which was conducted by an angiologist. Ultrasound was carried out with commercial devices, e.g., LOGIQ E9, and Vivid E9 XDclear (GE Healthcare Germany, Solingen/München, Germany). Superficial vein thrombosis or muscle vein thrombosis was not rated as DVT.

Included data

In addition to the presence of a PFO and DVT, the following patients’ characteristics were extracted from medical records: Demographic factors (age and sex), individual cardiovascular risk factors (arterial hypertension, hyper-/dyslipidemia, diabetes mellitus, nicotine consumption, atrial fibrillation), scores describing the previous general condition and the short-term functional outcome, i.e., modified Rankin Scale (mRS) [ 19 ] prior to the event (pre-mRS) and at hospital discharge, and National Institutes of Health Stroke Scale (NIHSS) [ 20 ] at admission and at discharge, existing medications affecting the coagulation system, and whether intravenous thrombolysis or endovascular therapy, i.e., mechanical recanalization, had been performed. Stroke etiology was classified according to the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria [ 21 ], added by the type “arterio-arterial embolism” to better describe the situation of a likely embolic event due to atherosclerosis in terms of plaque formation, usually located at the carotid arteries but not fulfilling the criteria of a stenosis with at least 50% or an occlusion.

Among well-established scores describing the risk for a DVT and the probability for a causal relationship between PFO and stroke, the Wells score [ 22 ] in its simplified version with one point for each criterion and the Risk of Paradoxical Embolism (RoPE) score [ 23 ] were used. Information on previous DVT, immobilization in the last 30 days before the qualifying cerebral event, current or past cancer, and current pulmonary embolism were included to assess the individual risk of thrombosis.

Clinical characteristics were calf compression pain and calf circumference difference. Laboratory parameters included, if available, D-dimer, C-reactive protein (CRP), leukocyte count, genetic thrombophilia (heterozygosity or homozygosity for prothrombin or factor V Leiden mutation), lupus anticoagulans-specific activated partial thromboplastin time (LA-specific aPTT), protein C, protein S, antinuclear antibodies (ANA), antibodies against beta-2-glycoprotein, cardiolipin, double strand DNA (dsDNA), nucleosomes, and histones were considered.

Statistical analyses

Analyses were performed with SPSS software package version 29.0 (IBM corp., Armonk, NY, USA) and R Statistical Software [ 24 ] with R Studio [ 25 ]. Considering the sample size, non-parametric testing was applied for testing statistical significance between groups, including Mann-Whitney-U Test and Chi-square test or Fisher’s exact test. If suitable, odds ratios (OR) and 95% confidence intervals (CI) were calculated to describe the probability for the existence of a DVT under specific conditions. Further, a multivariate logistic regression model was built with stepwise backward selection using p -value and Akaike Information Criterion. Generally, a p -value of < 0.05 was considered statistically significant.

Of 388 patients identified, cases with stroke mimics, uncertain TIA, and echocardiographic findings indicating other (atrial) septal defects than typical PFO were excluded. Consequently, a total of 339 patients with PFO were included in the study, while subgroups of stroke and TIA patients comprised of 294 and 45 patients.

Characterization of patients with stroke or TIA and concomitant PFO

Patients’ characteristics of the overall cohort and with reference to the subgroups stroke and TIA are shown in Table  1 . Thereby, patients with cerebral ischemia and evidence for PFO exhibited a mean age of about 61 years, were more often male (61.1%), and had higher rates of arterial hypertension and hyperlipidemia. Most patients were classified to “arterio-arterial embolism” etiology, followed by “undetermined/competing” etiology.

Patients with stroke or TIA did not differ significantly regarding sociodemographic factors, i.e., age and sex, and vascular risk factors, i.e., arterial hypertension, diabetes, hyperlipidemia, and atrial fibrillation ( p -values 0.254–0.852). Compared to TIA patients, a numerically increased proportion of stroke patients presented with nicotine consumption ( p  = 0.064). Stroke patients exhibited an increased NIHSS at hospital admission ( p  < 0.001) and an increased pre-mRS ( p  < 0.001) compared to TIA patients, indicating more severe clinical symptoms at the time of cerebral ischemia and a poorer condition before the event. As expected, the stroke and TIA group differed regarding the short-term outcome: As patients with TIA naturally presented no impairment at hospital discharge, the stroke cohort showed minor neurological deficits and a relatively low disability indicated by low levels of NIHSS ( p  < 0.001) and mRS ( p  < 0.001). Regarding the etiology of cerebral ischemia, stroke and TIA patients did not differ significantly with reference to the used adapted TOAST criteria ( p  = 0.284). “Undetermined/competing” etiology was numerically more often in TIA patients, while “cardioembolism” was numerically more often in stroke patients. Regarding the pre-existing medical treatment, stroke and TIA patients did not differ significantly ( p  = 0.895), while most patients had no coagulation-modifying medication before admission.

As all Patients included in this study presented a PFO, whose detection is naturally easier on transesophageal echocardiography (TEE), a high proportion of stroke (98%) and TIA (100%) patients had this diagnostic investigation done during hospital stay.

Rate of DVT

Compression ultrasonography of the lower limbs was conducted in 64% of the overall study group and a relatively wide temporal range of 1 to 15 days from hospital admission. Ultrasound examination was done significantly more often in stroke (66.7%) than in TIA (46.7%) patients ( p  = 0.016). In the overall study group comprising stroke and TIA patients with PFO, DVT was detected in 17 out of 339 cases (5%). For further calculations, only patients who underwent compression ultrasonography were considered. In those 217 patients, DVT was detected in 17 cases (7.8%). Remarkably, DVT was only found in stroke patients covering a group of 196 cases (8.8%), while compression ultrasonography performed in 21 TIA patients with PFO did not show evidence of DVT (0%). Despite this numerical difference in the rate of DVT among stroke and TIA patients examined with compression ultrasonography, statistical significance was not reached ( p  = 0.169). Regarding the dimension and location of DVT, of the 17 patients with DVT, 10 (58.8%) had a 1-level thrombosis, and 7 (41.2%) had a 2-level thrombosis. There were no 3- or 4-level thromboses. Of the 1-level thromboses, 6 (60%) were localized in the lower leg, 1 (10%) in the popliteal region, 2 (20%) in the thigh region, and 1 (10%) in the pelvic area. Regarding the 2-level thromboses, 4 (57.1%) were located distally in the lower leg and popliteal region and 3 (42.9%) in the thigh and popliteal or pelvic region. Regardless of the level, 10 of the 17 (58.8%) thromboses were distal and 7 (41.2%) proximal.

Parameters associated with DVT

To explore parameters that may help to identify DVT in patients with PFO, the 17 cases with diagnosed DVT were compared with 200 cases without evidence for DVT by compression ultrasonography.

Regarding demographic factors, patients with DVT were numerically older than those without (Fig.  1 ), failing statistical significance ( p  = 0.146). Further, sex did not differ significantly between patients with and without DVT ( p  = 0.226). Among clinical characteristics, patients with DVT exhibited a more severe neurological deficit as indicated by an increased NIHSS at hospital admission compared to those without DVT ( p  = 0.006). Regarding preexisting medications, patients with DVT compared to those without DVT did not differ concerning the existence of any medication affecting the coagulation system (17.6 vs. 25.5%; p  = 0.5723).

Comparison of age, National institutes of Health Stroke Scale (NIHSS) at hospital admission, Wells score, and RoPE score in stroke and TIA patients with and without deep vein thrombosis (DVT). Bars indicate mean values, added lines indicate standard error. **: p  < 0.01, ***: p  < 0.001. Number of patients in subgroup analyses (DVT/no DVT): age n  = 17/ n  = 200, NIHSS n  = 17/ n  = 200, Wells score n  = 17/ n  = 200, and RoPE score n  = 17/ n  = 200

Concerning already established approaches describing the risk for DVT (Fig.  1 ), an increased Wells score was found in stroke patients with PFO and concomitant DVT when compared to those without DVT ( p  < 0.001). Remarkably, a one-point increase in Wells score elevated the risk of DVT by 395% (OR 4.95, 95%-CI 2.73–10.52). Concerning the RoPE score, only 2 of the 17 patients (11.8%) with evidence of DVT had a score of 7 or higher, while 15 of the 17 patients (88.2%) had a score below 7. In the study group that is unselected for the cause of the ischemic event, the RoPE score did not differ significantly between patients with and without DVT ( p  = 0.360). Regarding anamnestic information covering the individual risk of thrombosis, patients with DVT more frequently had any type of cancer (23.5 vs. 9.5%; p  < 0.001; OR 2.93, 95%-CI 0.77–9.28) and a history of DVT in the past (23.5 vs. 3.0%; p  < 0.001; OR 9.95, 95%-CI 2.31–39.52). Also, patients with current DVT more often provided a coincident pulmonary artery embolism when compared to those without DVT (17.6 vs. 1% p  < 0.001; OR 21.21, 95%-CI 3.27–171.52). If patients were immobilized in the last 30 days before the cerebrovascular event, DVT was detected more often than without prior immobilization (11.8 vs. 3.5%; p  < 0.001; OR 10.36, 95%-CI 3.07–33.73).

In clinical assessments, patients with DVT compared to those without DVT more often presented calf compression pain (11.8 vs. 0.0%; p  = 0.006) and calf circumference difference (23.5 vs. 0.01%; p  < 0.001; OR 61.23, 95%-CI 8.35–1245.54).

Regarding laboratory parameters (Fig.  2 ), stroke patients with evidence of DVT, compared to those without, presented increased levels of D-dimer ( p  = 0.01), CRP ( p  = 0.038; OR 3.41, 95%-CI 1.25–9.81 for cut-off at 5 mg/L), and LA-specific aPTT ( p  = 0.032; OR 4.85, 95%-CI 1.89–17.06 for > 35 s.), while protein S was decreased ( p  = 0.015; OR 4.40, 95%-CI 1.04–16.76 for < 74%). However, patients with DVT were characterized by numerically increased leucocyte counts and levels of protein C without statistical significance ( p  = 0.249; p  = 0.367). Remarkably, genetic thrombophilia was more often detected in patients with DVT as compared to those without DVT (42.9 vs. 7.6%; p  = 0.010; OR 9.15, 95%-CI 1.48–55.02). Among antibodies, patients with DVT and those without DVT did not differ for ANA ( p  = 0.916), and antibodies directed against dsDNA ( p  = 0.139), nucleosomes ( p  = 0.213), histones ( p  = 0.058), beta-2-glycoprotein IgG ( p  = 0.572), beta-2-glycoprotein IgM ( p  = 0.614), cardiolipin IgG ( p  = 0.837), and cardiolipin IgM ( p  = 0.884).

Comparison of selected laboratory parameters in stroke and TIA patients with and without deep vein thrombosis (DVT). Bars indicate mean values, added lines indicate standard error. *: p  < 0.05. CRP: C-reactive protein, LA-specific aPTT: lupus anticoagulant-specific activated partial thromboplastin time. Number of patients in subgroup analyses (DVT/no DVT): max. D-dimer n  = 3/ n  = 52, CRP n  = 17/ n  = 200, leucocyte count n  = 17/ n  = 200, LA-specific aPTT n  = 12/ n  = 117, protein S n  = 11/ n  = 113, and protein C n  = 11/ n  = 114

A multivariate logistic regression model with DVT as the response variable and all formerly mentioned significantly differing parameters as predictors was applied, but the full model did not yield significant results. Remarkably, a stepwise backward selection model revealed the Wells score as a significant predictor for DVT in patients with cerebral ischemia and concomitant PFO (adjusted OR 35.46, 95%-CI 4.71–519.92).

This study aimed to characterize patients with stroke or TIA and concomitant PFO and also explore the rate of DVT and associated parameters, which might help to guide additional examinations, i.e., ultrasonography. Data from standard care of patients with cerebral ischemia and echocardiographically confirmed PFO were used, which might help to overcome limitations from earlier studies on highly selected populations.

With about 61 years of age, patients in this study were older compared to earlier investigations focusing on PFO closure, with about 43 and 45 years, respectively [ 3 , 4 ]. Also, in studies primarily focusing on diagnostic proceedings for thrombosis in conjunction with PFO, patients were typically younger with about 47 and 57 years, respectively [ 26 , 27 ]. The unselected nature of the cohort underlying this study is further emphasized by the finding that most events were etiologically classified to “arterio-arterial embolism”, while previous investigations, e.g., a PFO closure trial [ 3 ], excluded patients with causes other than the PFO, and non-interventional studies often focused on cryptogenic stroke [ 26 ]. Regarding subgroups stroke and TIA, both with concomitant PFO, the present study did not provide significant differences among age, sex, and typical risk factors. Following local standards, more than half of patients underwent compression sonography of the lower limbs, which was, however, more often performed after stroke when compared to TIA.

Focusing on patients with PFO and performed compression sonography of the lower limbs, the DVT rate in this study (7.8%) is in good accordance with earlier investigations. For example, DVT of the lower limbs was found in 7.1% of 131 patients with ischemic stroke or TIA with concomitant PFO [ 27 ]. Also, DVT was found in 7% of 293 patients with ischemic stroke and concomitant PFO [ 28 ]. In addition, DVT was detected in 8.7% of 323 patients in a study that included stroke cases regardless of PFO [ 29 ]. In these studies, screening for DVT was done by ultrasonography and magnetic resonance venography of the pelvis. Remarkably, the present study used compression ultrasonography only, which resulted in a comparable proportion of patients. This observation leads to the assumption that the use of pelvic magnetic resonance venography, in addition to compression ultrasonography, might have resulted in a higher rate of thrombosis in the population underlying this study. However, the German guideline recommends the complete compression sonography of deep and superficial veins of the whole leg [ 30 ], as done in this study. According to these guideline, imaging of pelvic veins is only recommended in case of suspicious ultrasound signals or symptoms indicating pelvic vein thrombosis or during pregnancy, which did not occur in our study group. As explorative studies described DVT rates between 7 and 10.5% in patients with stroke linked to PFO [ 13 ], significantly higher DVT rates reported in earlier studies might be related to methodological issues. In detail, one study found DVT in 27% of stroke patients [ 31 ], whereby the underlying population was relatively small, with only 37 cases, and those with an etiology classified other than cryptogenic were previously excluded. When focusing on subgroups of stroke and TIA, the present study identified DVT only in patients with stroke. One reason might be that TIA patients exhibited a healthier condition at the time of the cerebrovascular event and thus had a markedly lower risk for DVT, supported by the significantly lower pre-mRS compared to cases with stroke, as seen in this study. Another reason might be that the cohort of patients with TIA in this study was too small to yield cases with DVT.

Regarding parameters associated with DVT in patients with stroke or TIA and concomitant PFO, this study indicated an increased NIHSS at hospital admission, current or past cancer, a history of DVT, immobilization within the last 30 days, coincident pulmonary artery embolism, calf compression pain, and calf circumference difference as features that differ significantly between those with and without sonographic evidence. These observations are comparable with previous investigations in patients other than stroke or TIA. For example, a recent study in unselected patients identified malignancy (OR 2.84, 95%-CI 0.518–15.513), surgery (OR 2.66, 95%-CI 0.411–17.281), and trauma (OR 2.30, 95%-CI 0.452–11.648), the last two are usually accompanied by immobilization, as the three most frequent conditions associated with sonographically confirmed DVT [ 32 ]. Further, a study in patients with neurological diseases other than cerebrovascular events found malignant conditions associated with a high risk for DVT (OR 11.7, 95%-CI 1.0–301.4) [ 15 ].

Concerning laboratory findings, the present study revealed D-dimer, CRP, LA-specific aPTT, protein S, and genetic thrombophilia as parameters that differ significantly between patients with and without DVT. For D-dimer, comparable observations were made in a study including neurological patients other than cerebrovascular events (OR 5.7, 95%CI 2.1–16.7) [ 15 ], in two studies with stroke patients at the time of rehabilitation (OR 1.446, 95%-CI 1.130–1.849 [ 33 ], OR 2.283, 95%-CI 1.374–3.868 [ 34 ]), and in one study with stroke patients in the earlier stage (1.05, 95%-CI 1.00-1.09 per 1-μg/mL increase) [ 35 ]. For CRP, the present study revealed significantly higher CRP serum levels in patients with DVT compared to those without evidence of DVT. This is in good accordance with a previous survey comprising patients with stroke regardless of PFO, while cases with evidence for DVT had an increased CRP compared to those without [ 29 ].

Among established scores in the field of DVT and PFO, this study identified the Wells score as significantly increased in patients with DVT compared to those without, with a remarkable risk increase of about 400% for a one-point increase in the score. Even though it did not have such a strong association, the Wells score was also increased in cases with DVT in an earlier study, including 133 stroke patients [ 35 ]. Considering parameters identified in the present and previous studies, the finding that the Wells score might help to identify stroke patients with an increased risk of DVT seems plausible as the score combines conditions such as immobilization, malignancy, history of DVT, and difference in calf circumference. Collectively, regarding the cohort of patients with stroke or TIA and concomitant PFO, the Wells score appears suitable for clinical practice as a starting point guiding additional examinations, i.e., compression ultrasonography.

This study has some limitations: Due to its retrospective design and the use of routinely obtained data, some patients with PFO may have been missed, because TEE, which is known to be superior to transthoracic echocardiography (TTE) in detecting PFO [ 36 ], is typically performed more often in younger than in older patients. Not all patients with PFO had been examined by compression ultrasonography, further limiting the sample size and generalization of the findings. In addition, as the presence of DVT was based on ultrasound of the lower limbs, sites like deep pelvic and more proximally located veins, which might also represent potential sources of embolic events [ 27 ], are not considered. Since ultrasonography of the leg veins was usually performed not directly at hospital admission, it cannot be ruled out that some patients may have acquired deep vein thrombosis during their hospital stay. This could play a role, especially in severely affected patients who are subsequently immobilized. Although a remarkable number of patients was screened, the resulting cohort with concomitant PFO and DVT was relatively small and some laboratory parameters were available only in a few patients, limiting some statistical calculations, i.e., concerning diagnoses (stroke vs. TIA), clinical, and laboratory characteristics. For instance, a normal D-dimer was not seen in the group with DVT, which inhibited the calculation of OR and 95%-CI, while for other parameters, the skew in data might have increased ORs and upper limits of 95%-CI drastically. On the other hand, the emerging limitations clearly illustrate the challenges of investigations regarding PFO and DVT in patients with cerebrovascular events.

This study indicated a DVT rate of 7.8% in patients with cerebral ischemia and concomitant PFO, which needs to be considered when planning the individual diagnostic workup. A few anamnestic, clinical, and laboratory parameters were identified to be associated with an existing DVT. However, a multivariate regression model with stepwise backward selection identified the Wells score as a significant predictor of DVT. The Wells score thus seems to be suitable to guide additional examinations, i.e., compression ultrasonography for screening of DVT in patients with cerebral ischemia and concomitant PFO.

Data availability

Data underlying this study will be made available upon reasonable request to the corresponding author.

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Acknowledgements

Personnel of the University of Leipzig who is not mentioned in the list of authors but have contributed to the generation of the complex data set underlying this study are kindly acknowledged for the support.

Open Access funding enabled and organized by Projekt DEAL. This study was conducted without external funding.

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Department of Neurology, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany

Charlotte Huber, Richard Schmidt, Johann Otto Pelz & Dominik Michalski

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Stephan Stöbe, Andreas Hagendorff & Rolf Wachter

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Study design and regulatory affairs: DM, JOP, and CH. Generation of underlying data: DM, JOP, CH, AH, SS, KSM, KTH, and BI. Assistance in case identification: NvD. Data extraction: CH. Statistical calculations: CH, DM, and RS. Manuscript preparation incl. table and figures: CH and DM. Critical revisions to the manuscript: JOP, RW, NvD, KSM, KTH, SS, AH, and BI. Allauthors approved the submitted manuscript.

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Huber, C., Stöbe, S., Hagendorff, A. et al. Deep vein thrombosis in patients with stroke or transient ischemic attack presenting with patent foramen ovale: a retrospective observational study. BMC Neurol 24 , 295 (2024). https://doi.org/10.1186/s12883-024-03802-0

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Study Protocol

Protocol for Cerebellar Stimulation for Aphasia Rehabilitation (CeSAR): A randomized, double-blind, sham-controlled trial

Roles Project administration, Writing – original draft, Writing – review & editing

Affiliation Department of Physical Medicine and Rehabilitation, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America

Roles Project administration, Writing – review & editing

Current address: Independent Researcher, Salt Lake City, UT, United States of America

Current address: School of Medicine, New York Medical College, Valhalla, NY, United States of America

Roles Methodology, Writing – review & editing

Affiliation Johns Hopkins Biostatistics Center, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States of America

Roles Conceptualization, Methodology, Writing – review & editing

Affiliations Department of Physical Medicine and Rehabilitation, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America, Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America, Department of Cognitive Science, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, United States of America

Roles Conceptualization, Funding acquisition, Methodology, Supervision, Writing – review & editing

* E-mail: [email protected]

• Becky Lammers, 
• Myra J. Sydnor, 
• Sarah Cust, 
• Ji Hyun Kim, 
• Gayane Yenokyan, 
• Argye E. Hillis, 
• Rajani Sebastian

• Published: August 26, 2024
• https://doi.org/10.1371/journal.pone.0298991
• Reader Comments

In this randomized, double-blind, sham-controlled trial of Cerebellar Stimulation for Aphasia Rehabilitation (CeSAR), we will determine the effectiveness of cathodal tDCS (transcranial direct current stimulation) to the right cerebellum for the treatment of chronic aphasia (>6 months post stroke). We will test the hypothesis that cerebellar tDCS in combination with an evidenced-based anomia treatment (semantic feature analysis, SFA) will be associated with greater improvement in naming untrained pictures (as measured by the change in Philadelphia Picture Naming Test), 1-week post-treatment, compared to sham plus SFA. We will also evaluate the effects of cerebellar tDCS on naming trained items as well as the effects on functional communication, content, efficiency, and word-retrieval of picture description, and quality of life. Finally, we will identify imaging and linguistic biomarkers to determine the characteristics of stroke patients that benefit from cerebellar tDCS and SFA treatment. We expect to enroll 60 participants over five years. Participants will receive 15, 25-minute sessions of cerebellar tDCS (3–5 sessions per week) or sham tDCS combined with 1 hour of SFA treatment. Participants will be evaluated prior to the start of treatment, one-week post-treatment, 1-, 3-, and 6-months post-treatment on primary and secondary outcome variables. The long-term aim of this study is to provide the basis for a Phase III randomized controlled trial of cerebellar tDCS vs sham with concurrent language therapy for treatment of chronic aphasia.

Trial registration: The trial is registered with ClinicalTrials.gov NCT05093673 .

Citation: Lammers B, Sydnor MJ, Cust S, Kim JH, Yenokyan G, Hillis AE, et al. (2024) Protocol for Cerebellar Stimulation for Aphasia Rehabilitation (CeSAR): A randomized, double-blind, sham-controlled trial. PLoS ONE 19(8): e0298991. https://doi.org/10.1371/journal.pone.0298991

Editor: Dinesh V. Jillella, Emory University, UNITED STATES OF AMERICA

Received: February 23, 2024; Accepted: July 9, 2024; Published: August 26, 2024

Copyright: © 2024 Lammers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.

Funding: The trial is fully funded by the National Institute on Deafness and Other Communication Disorders (NIH/NIDCD) R56/R01 DC019639. The funders had and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Aphasia is a devastating outcome and one of the leading causes of disability following stroke. Aphasia adds substantial costs to the acute [ 1 ] and chronic [ 2 ] care of individuals with stroke and is an independent predictor of subsequent functional dependence and death [ 3 ]. Anomia or difficulty with naming is the most common deficit in individuals with aphasia. Currently, the most widespread rehabilitation approach for aphasia is speech and language therapy (SALT) [ 4 ]. Although the interventions to improve naming can have benefits [ 5 – 9 ], a substantial number of treatment sessions is usually required to show gains, particularly in individuals with chronic large left hemisphere stroke. Therefore, to address how the treatment of aphasia might be made more effective, researchers are now using an emerging, safe, non-painful, and low-cost brain stimulation method called transcranial direct current stimulation (tDCS) [ 10 ]. There is evidence that tDCS may be useful for enhancing the effects of behavioral aphasia treatment. Evidence is growing that the add-on use of tDCS can aid in the recovery of aphasia as highlighted by international recommendations [ 11 ]. However, there is a general lack of consensus regarding the optimal electrode montage for stimulation in post-stroke aphasia. Addressing this barrier is critical for successful clinical translation.

Stimulating the residual left hemisphere region is the most common approach based on the observation that optimal recovery involves the functional re-recruitment of the remaining left-hemisphere tissue [ 12 – 16 ]. However, encephalomalacia filled with cerebrospinal fluid at the site of stroke affects the electrical current flow, reducing the exposure of the targeted perilesional tissue to stimulation [ 17 ]. This issue makes selection of optimal electrode locations in the left hemisphere difficult. Approaches to address this issue involve advanced electrical field modeling methods [ 18 – 20 ] or individualized electrode placement based on pre-treatment functional magnetic resonance imaging (fMRI) scans so that stimulation targets residual functional tissue [ 21 – 24 ]. However, advanced electrical field modeling and fMRI are cost-intensive and require substantial technological expertise. This would limit the incorporation of tDCS into routine speech language pathology clinical practice. We propose a novel approach to augment aphasia treatment by stimulating the right cerebellum. The right cerebellum is not only involved in cognitive and language functions (see [ 25 – 27 ] for reviews) but is also distant enough from typical stroke locations associated with aphasia that electrical current flow patterns are unlikely to be affected by the encephalomalacia [ 17 ]. In addition, this approach is suitable for patients who have large left hemisphere strokes and aphasia associated with bilateral hemispheric strokes.

In 2017, our group published the first study showing that cerebellar tDCS has the potential to augment aphasia treatment in a participant with bilateral middle cerebral artery infarct resulting in aphasia [ 28 ]. Subsequently, another group, utilizing a crossover study design, showed that 5 sessions of cathodal cerebellar tDCS coupled with language treatment improved verb generation immediately post-treatment in chronic post-stroke aphasia [ 29 ]. In a follow up study, we conducted a randomized, double-blind, sham controlled, within-subject crossover study in 24 chronic stroke participants with aphasia [ 30 ]. We also investigated whether there are any differences in anodal versus cathodal cerebellar tDCS on naming performance as prior studies in healthy controls have shown beneficial language effects for anodal and cathodal cerebellar stimulation [ 17 , 31 – 33 ]. Participants received 15 sessions of anodal (n = 12) or cathodal (n = 12) cerebellar tDCS + computerized aphasia therapy in Phase 1 followed by sham + computerized aphasia therapy in Phase 2, or the opposite order. The results of our study revealed several important findings, which have significant implications for the proposed study. First, we found that cerebellar tDCS significantly improved naming in trained (Naming 80) and untrained (Philadelphia Naming Test, PNT [ 34 ]) items immediately post-treatment, and the significant improvement in untrained naming was maintained at two months post-treatment. Second, we found that participants receiving cathodal stimulation showed significantly greater gains (compared to sham) in naming than participants receiving anodal stimulation, indicating that cathodal stimulation might be more favorable than anodal stimulation to augment aphasia treatment. Thus, these results indicate that cathodal cerebellar tDCS combined with language treatment has the potential to augment aphasia treatment.

tDCS is believed to enhance neural plasticity by temporarily modulating resting membrane potentials of neurons in targeted areas [ 35 , 36 ]. Anodal stimulation may lead to depolarization of the neuronal membranes resulting in greater excitability, whereas cathodal stimulation may lead to hyperpolarization resulting in lower excitability. Because the cerebellar cortex is highly convoluted and the neuronal architecture is different from cortical circuits, the polarity of cerebellar tDCS effects is not necessarily the same as the polarity of cortical tDCS effects. Animal and human studies indicate that cerebellar tDCS is most likely to produce its effects by polarizing Purkinje cells ‐ the inhibitory output neurons of the cerebellar cortex ‐ and thereby changing the levels/pattern of activity in the deep cerebellar output nuclei, which are the efferent targets of the Purkinje cells [ 37 , 38 ]. Critically, one of the deep cerebellar nuclei, the dentate nucleus, has a disynaptic excitatory connection through the thalamus to the cortical language areas. Based on this known circuitry, we hypothesize that a single session of right cathodal cerebellar stimulation will result in transient depression of Purkinje cell activity, thereby reducing the inhibitory signals that the cerebellum sends to the cortical language areas. Anodal cerebellar stimulation will exert the opposite effect, i.e., it will increase the discharge from the Purkinje cells, thereby increasing the inhibitory signals the cerebellum sends to the cortical language areas. Thus, it is plausible that multiple sessions of cathodal cerebellar tDCS will provide cortical excitation, thereby facilitating the engagement of the residual left hemisphere language areas.

In this proposal, we will combine cerebellar tDCS with semantic feature analysis (SFA) treatment for post-stroke aphasia (see [ 39 – 43 ] for reviews regarding SFA). SFA is a semantically based treatment approach for naming deficits. SFA was chosen for this study for three main reasons (1) SFA has a strong potential for promoting acquisition and generalization effects for participants with anomia, (2) SFA is an effective therapy for treating naming deficits for individuals with a range of aphasia types and severities, and (3) SFA is a treatment that is frequently used by practicing speech-language pathologists (SLPs). The driving premise of SFA treatment is that when individuals generate semantic features of a target word (i.e., accessing their semantic network), they improve their ability to retrieve the target because they have strengthened access to its conceptual representation [ 41 , 44 ]. The theoretical mechanism by which SFA promotes generalization comes from the spreading activation theory [ 45 ] which posits that accessing/activating a particular lemma (or its features) results in activation of the lemmas of semantically related concepts. Prior studies provide strong compelling evidence that the right cerebellum, the target of our tDCS treatment, is a critical structure involved in semantic processing and naming [ 25 – 27 , 46 – 48 ].

Here we describe a protocol for an ongoing randomized, double-blind, sham-controlled study of cerebellar tDCS for augmenting anomia therapy in chronic aphasia. Participants are enrolled parallelly at two sites within the Johns Hopkins Rehabilitation Network: Johns Hopkins Hospital and Howard County General Hospital. We hypothesize that 15 sessions of cathodal cerebellar tDCS plus SFAwill be associated with greater improvement in naming untrained pictures (as measured by the change in Philadelphia Picture Naming Test, PNT [ 34 ], 1-week post-treatment, compared to sham plus SFA. For secondary outcomes, we hypothesize that cathodal cerebellar tDCS plus SFAwill result in greater improvement in discourse (as measured by change in total content units (CU) and syllable per CU in picture description [ 49 ] and greater improvement in functional communication skills (as measured by change in Communication Activities of Daily Living–CADL-3 [ 50 ] compared to sham plus SFA. We also hypothesize that 15 sessions of cathodal cerebellar tDCS plus SFA will result in greater improvement on the Western Aphasia Battery-Revised (WAB-R) [ 51 ], General Health Questionnaire (GHQ)-12 [ 52 ], and Stroke and Quality of Life Scale (SAQOL-39) [ 53 ] compared to sham plus SFA.

A second aim is to identify whether neural (functional and structural) biomarkers and linguistic characteristics can predict response to cerebellar stimulation and SFA treatment. Our prior work in cerebellar tDCS in aphasia has shown that individual response to tDCS treatment is highly variable. However, little is known about how factors related to imaging and linguistic characteristics combine to induce treatment responsiveness. We will carry out resting state functional magnetic resonance imaging (rsfMRI), diffusion tensor imaging (DTI), high resolution structural imaging, and detailed linguistic testing before the start of treatment to determine whether these factors can predict response to cerebellar tDCS and/or SFA. This exploratory aim may identify stroke patients who are mostly likely to benefit from cerebellar tDCS and/or SFA. This result may have significant implications for designing a Phase III randomized controlled trial.

Materials and methods

This study, Cerebellar Stimulation for Aphasia Rehabilitation (CeSAR), is a Phase II trial of cathodal cerebellar tDCS plus SFA treatmentvs. sham plus SFA treatment, evaluated in double-blind, randomized, sham-controlled design in chronic stroke. Participants with chronic aphasia are enrolled at two sites within the Johns Hopkins Rehabilitation Network at least 6 months after the onset of stroke. The two sites will be the Johns Hopkins Hospital and Howard County General Hospital. Sixty participants are expected to enroll over five years. Enrollment for this study began on October 25, 2021. The SPIRIT schedule of enrollment, interventions, and assessments is included as Fig 1 . The World Health Organization Trial Registration Data Set compiled by ClinicalTrials.gov (NCT05093673) is reproduced in Table 1 (SPIRIT Item 2b). The SPIRIT checklist is included in S1 File . A full accounting of evaluations and unabridged protocol approved by the IRB is available in S2 File (January 29, 2024) and important protocol modifications will be available from the corresponding author and by viewing the ClinicalTrials.gov study entry. A sample consent form is included in S3 File .

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Patient population-inclusion and exclusion criteria

Participants must be >6 months post ischemic or hemorrhagic left-hemisphere stroke and diagnosed with post-stroke aphasia and naming impairment using the Western Aphasia Battery-Revised (WAB-R). They must also be 18 years or older, and English-speaking by self-report with no lesions on the right cerebellum, with no previous neurological disorder other than stroke, or other neurodegenerative or psychiatric disorders. Individuals with seizures within the previous 6 months, those taking medications that lower the seizure threshold (e.g., methylphenidate) or N-methyl-D-aspartate (NMDA) antagonists (e.g., memantine), and those with a history of brain surgery or with any metal in the head will be excluded. We will also exclude those with uncorrected hearing or vision loss by self-report, those who score >80% on the Philadelphia Naming Test (PNT) at baseline, and those with severely impaired auditory comprehension and/or severely limited verbal output (lower than 2 on the Auditory Comprehension subscore on the WAB-R and/or lower than 2 on the Spontaneous Speech rating scale on the WAB-R, respectively). Individuals with severe claustrophobia, cardiac pacemakers or ferromagnetic implants, and pregnant women will be excluded from the MRI portion of the study.

Inclusion criteria.

• Chronic ischemic or hemorrhagic left hemisphere stroke
• Fluent speaker of English by self-report
• Age 18 or older
• 6 months post onset of stroke
• Diagnosis of aphasia and naming impairment using the Western Aphasia Battery-Revised

Exclusion criteria.

• Lesion in the right cerebellum
• Previous neurological disorder (other than stroke) affecting the brain, or any other neurodegenerative disorder or psychiatric disorder
• Seizures during the previous 6 months
• Uncorrected visual loss or hearing loss by self-report
• Use of medications that lower the seizure threshold (e.g., methylphenidate, amphetamine salts)
• Use of N-methyl-D-aspartate (NMDA) antagonists (e.g., memantine)
• >80% correct response on the Philadelphia Naming Testing at baseline
• History of brain surgery or any metal in the head
• Severely impaired auditory comprehension (lower than 2 on the Comprehension subscore on the Western Aphasia Battery-Revised)
• Severely limited verbal output (lower than 2 on the Spontaneous Speech rating scale on the Western Aphasia Battery-Revised)
• Individuals with severe claustrophobia, cardiac pacemakers or ferromagnetic implants, and pregnant women will be excluded from the MRI portion of the study.

Informed consent

A signed and dated informed consent form will be obtained from each participant. For participants who cannot consent for themselves, a legally authorized representative, such as a legal guardian or power of attorney, must sign the consent form. The consent form will describe the purposes, procedures, risks, and benefits of participation in the study, as well as the participant’s ability to withdraw consent at any time without retaliation or impact on clinical care. A copy will be given to each participant or legally authorized representative.

Once the consent form has been signed, participants will be assigned a temporary identification number for the purposes of initial screening.

All research staff authorized to obtain informed consent will have completed the Miami CITI course in the Responsible Conduct of Research and Protection of Human Subjects prior to their involvement with the study. Furthermore, they will be oriented to the study and trained by the study PI and study co-investigators who have all had extensive training and experience in the ethical and practical aspects of informed consent procedures.

Participant confidentiality

Participation in this study should not put participants in any legal risk, even in the case of a breach of confidentiality. We will undertake every effort to keep the information in the study confidential. Participants will be assigned a code number in order to keep protected health information confidential. Consent forms and source documents will be maintained at the PI lab in a locked cabinet. All digital data will be done using participant identification numbers only and will be stored on a password-protected and encrypted format in a manner that is Johns Hopkins IRB compliant. This will include the Clinical Research Management System (CRMS), Research Electronic Data Capture (REDCap), and Johns Hopkins Microsoft One Drive. All are web-based applications designed to organize and streamline clinical research management. CRMS is integrated with Epic, Hopkins enterprise EMR, as well as Johns Hopkins IRB. This integration improves communication among study team members, stores subject enrollment information in a secure location, assists with recruitment, and allows research results to be promptly incorporated into the EMR. Everybody involved in the study will have completed the appropriate HIPAA training and are fully aware of confidentiality issues. No names will be included in any publications resulting from this work.

Randomization

Prior to randomization, all eligible participants will receive comprehensive language and cognitive evaluations as well as MRI for those who consent and who have no contraindication. Participants will be randomly assigned 1:1 (cerebellar cathodal tDCS plus SFA treatment or sham tDCS plus SFA treatment). The randomization is stratified by study site (JHH vs Howard County), aphasia type (fluent vs. non-fluent, classified using WAB-R), and aphasia severity. Aphasia severity will be classified using WAB-R Aphasia Quotient in 4 categories (very severe aphasia: 0–25, severe aphasia: 26–50, moderate aphasia: 51–75, and mild aphasia: 76–93.8). Covariate-adaptive randomization method developed by Pocock and Simon, 1975 [ 54 ] will be implemented in REDCap. This method ensures balance on important baseline covariates by treatment arm by calculating the difference in these covariates (site, aphasia type and severity) each time a participant needs be randomized and then randomizes with high probability (80%) to the arm that corrects the imbalance on covariates.

The SLP will enter the baseline and eligibility information of a participant prior to enrollment on REDCap. If the participant’s eligibility is confirmed, then the algorithm implemented in REDCap will evaluate the treatment arm distribution in participants already randomized and then generate treatment allocation group (sham or tDCS) based on the randomization scheme. Each participant will receive a unique six-digit codes (provided by the manufacturer of the tDCS stimulator), which will instruct the stimulator to deliver either active stimulation or placebo (sham). These codes will be entered into REDCap prior to starting the study. The study coordinator will enter the codes in REDCap.

Both groups will receive semantic feature analysis treatment, a commonly used treatment for naming deficits in aphasia. It is currently unknown whether or not cerebellar tDCS augments the effect of semantic feature analysis in the chronic phase after stroke. Therefore, a sham group is justified.

The study is to be conducted in a double-blind manner. All participants, the members of the study team who administer the assessments, those who administer treatments, as well as the study biostatistician performing the statistical analyses will be blinded.

The MRI scans will be performed prior to the start of the study on a 3T Philips system at the F.M. Kirby Center at the Kennedy Krieger Institute. Imaging will be done for patients who have no MRI contraindications. Imaging will include structural and functional scans. Structural scans will include high resolution T1 and T2 weighted images, Fluid Attenuation Inversion Recovery (FLAIR) scans, and Diffusion Weighted Imaging (DWI) images. Functional scan will include resting state functional MRI.

Participants will receive 15 sessions of SFA treatment (3–5 sessions per week over the course of 3 to 5 weeks) and each session will be 60 minutes. Prior to the start of treatment, participants will be randomly assigned to receive either sham plus SFA or active tDCS plus SFA.

The SLP will start the Semantic Feature Analysis Treatment. Participants will receive SFA treatment for 60 minutes and tDCS for the first 25 minutes. SFA treatment employed in this study will include 50 items and their relevant features from eight semantic categories. Items included in each participant’s treatment list will be determined based on performance on a picture-naming task. The naming task will consist of 200 items across eight semantic categories (food [fruits, vegetables], animals, transportation, clothing, furniture, music, sports, toys). The naming task will be administered once. To qualify for treatment, an item must be named incorrectly. To avoid effects of repeated exposure, items included on the naming task will be constrained such that they do not occur in the primary outcome variable (PNT).

Therapy tasks will be administered through a computer with clinician assistance using Microsoft PowerPoint. Participants will be trained on 7–12 items per session depending on each participant’s aphasia severity. The treatment protocol will be adapted from Doyle, Dickey and colleagues [ 55 , 56 ]. The treatment will proceed according to a series of steps including naming aloud the target picture, generating semantic features, naming aloud the target picture again, and generating a sentence using the target word. Participants will be asked to generate semantic features for each target picture in five categories: group [superordinate category], function [use/action], description [physical properties], context [location], and other/personal [association]. A three-level cueing hierarchy will be used to elicit features, consisting of general prompt (e.g., “How would you describe this?”), followed by a relevant directed question (e.g., “What does this feel like?”) and a binary forced-choice question (e.g., “Is this item smooth or rough?”).

tDCS will be delivered for 25 minutes using the Soterix Medical 1x1 Clinical trials device. Soterix 1×1 CT is the most advanced and customizable system for true double-blind control trials. Consistent with other studies on cerebellar tDCS [ 28 – 30 , 57 ], the current study will utilize 2 mA of cathodal tDCS stimulation generated between two 5 cm x 5 cm saline-soaked sponges. The active electrode (cathode) will be placed on the right cerebellar cortex, 1 cm under and 4 cm lateral to the inion (approximately comparable to the projection of cerebellar lobule VII onto the scalp [ 31 ]. The reference electrode (anode) will be placed over the right shoulder. For both tDCS and sham interventions, current will be ramped up over a 15 second interval at stimulation onset, eliciting a transient tingling sensation that effectively blinds the participant to treatment condition [ 58 ]. After the ramp up, in the sham condition, current intensity will be ramped down over a 15 second interval to 0 mA. Participants will rate their pain levels at the beginning and end of stimulation with the Wong-Baker FACES Pain Rating Scale (wongbakerfaces.org) [ 59 ]. In each session, participants will be asked to inform the SLP about any side effects. Participants generally tolerate tDCS well, the main reported side effects being initial tingling or itching sensations at the beginning of the session for some participants [ 60 ]. Stimulation (for both tDCS and sham conditions) will start at the same time as the aphasia treatment. Aphasia treatment will continue for another 35 minutes after the completion of 25 minutes of real tDCS or sham tDCS for a total of 60 minutes per session.

Intervention for a participant will be discontinued if any of the following criteria are met: Participants will be removed from the study if they are unable to comply with task instructions or tolerate the tDCS procedure.

When the study ends, participants will continue to receive management with Dr. Argye Hillis (study neurologist) or their own neurologist as usual (generally follow-up visits approximately every 12 months). If a patient’s participation in the study ends prematurely s/he will still receive care as before. In sum, termination of the study or termination of participation in it will not affect regular therapy he or she may be receiving.

Primary outcome

The primary outcome will be defined as the change in accuracy of naming untrained pictures measured by the Philadelphia Naming Test (PNT), one week after the end of semantic feature analysis (SFA). Although our previous study [ 30 ] showed that the significant improvement in untrained naming (PNT) with cathodal cerebellar tDCS was maintained at two months post-treatment, we choose to measure untrained naming one week post-treatment in the current study because we are using a different study design and naming treatment.

Secondary outcomes

In addition to the primary outcome, several secondary analyses will be conducted.

• Trained Picture Naming. We will assess if tDCS has an effect on naming items trained during treatment (trained picture naming). In addition to assessing changes in correct naming, we will also evaluate treatment-related changes in naming errors to provide additional insight into naming recovery following cerebellar tDCS. Naming errors will be categorized as 1) semantic paraphasias; 2) phonological paraphasias; 3) mixed (phonological and semantic) paraphasias; 4) non-responses; and 5) unrelated responses.
• Discourse. We will assess change in discourse abilities, as measured by the change in the total Content Units (CU) and syllable per CU produced by the participants during connected speech. Participants will be required to describe the Cookie Theft Picture from the Boston Diagnostic Aphasia Examination.
• Functional Communication Skills. We will also measure changes in everyday functional communication skills assessed with the Communication Activities of Daily Living, third edition (CADL-3).
• Finally, we will administer 3 tests from the Research Outcome Measurement in Aphasia-Core Outcome Set (ROMA-COS). The WAB-R will be administered as a part of the baseline testing. We will also assess changes in emotional wellbeing (measured by General Health Questionnaire (GHQ)-12 and quality of life (measured by Stroke and Aphasia Quality of Life Scale (SAQOL-39).

All outcome variables (primary and secondary) will be administered at baseline (pre-treatment), 1 week, one month, three months, and six months after the completion of the treatment.

Data collection and quality assurance

All research staff authorized to obtain informed consent will have completed the Johns Hopkins University School of Medicine’s required training in the Responsible Conduct of Research and Protection of Human Subjects prior to their involvement with the study. Furthermore, they will be oriented to the study and trained by the study PI and study co-investigators who have all had extensive training and experience in the ethical and practical aspects of informed consent procedures.

The PI as well as the SLPs who administer baseline testing, treatments, and follow-up testing will be blinded to participant treatment assignments (described in full in the protocol provided in the S2 File ). Participants will be assigned a code number in order to keep protected health information confidential. Consent forms and source documents will be maintained at the PI lab in a locked cabinet. All digital data will be done using participant identification numbers only and will be stored on a password-protected and encrypted format in a manner that is Johns Hopkins IRB compliant.

The PI (an ASHA certified SLP) will provide training to the two ASHA certified SLPs for scoring and administration of the assessment materials as well as the SFA treatment protocol. To ensure quality control, all assessment sessions and part of the treatment sessions will be videotaped. The PI will create a written protocol for clinicians regarding assessment and scoring, and to ensure consistency of delivery and adherence to SFA treatment protocol. This will reduce clinician-to-clinician variability, clinician drift, and contamination.

With respect to language assessment, the PI will be present for the first few assessment sessions to assure fidelity during assessment. This will be followed by regular monitoring to ensure adherence to assessment administration procedures. All deviations will be reviewed and clarified with the clinician to ensure that adherence is improved in subsequent sessions. Each clinician will have 20% of their total assessment sessions monitored quarterly for accurate implementation.

With respect to SFA treatment, the PI will be present for the initial few sessions to assure fidelity during treatment implementation. Following this, treatment fidelity will be monitored on a weekly basis by a member of the study team who is not providing treatment by reviewing short video-recorded segments of treatment for adherence to the SFA protocol using a Treatment Fidelity Checklist. All deviations will be reviewed and clarified with the treating clinician to ensure that adherence is improved in subsequent sessions. When session monitoring detects < 1 deviation across three consecutive samples, sessions will be monitored once bi-weekly for the remainder of the 3–5-week (3–5 sessions per week) treatment period. If session monitoring detects >1 deviations across three consecutive samples, sessions will be monitored daily until deviation is less than one. The PI and research team members meet weekly (or more often) to discuss questions about and implementation of the protocol.

To minimize the need for research-only in-person visits, telemedicine visits will be substituted for portions of clinical trial visits where determined to be appropriate and where determined by the investigator not to increase the participants risks. For the current study, we will utilize telemedicine visits when appropriate for consenting and for all the assessments visits (visits 1–3, 20–23). Prior to initiating telemedicine for study visits the study team will explain to the participant what a telemedicine visit entails and confirm that the study participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA compliant method approved by the Johns Hopkins Health System and within licensing restrictions. Similar to in-person visits, assessment fidelity as well as regular monitoring will be conducted for telemedicine visits to ensure adherence to assessment administration procedures.

Sample size estimates

Sample size was determined based on the PI’s prior crossover trial data [ 30 ]. That data was used to estimate the variability of untrained naming score. Enrolling 52 participants (26 per group) will give us 80% statistical power to detect 0.7 SD difference in change in accuracy of naming untrained items at 1-week post-treatment between the study arms. This was done using Wald test for group assignment coefficient in linear regression at 0.1 level of statistical significance. The effect size (0.7SD) is a bit conservative compared to the difference observed on group comparison for 21 participants (10 in tDCS and 11 in sham) in the crossover trial data, when the tDCS was administered in Phase 1. We propose to enroll 60 participants to account for 10% attrition. However, if we have trouble meeting recruitment/retention goals, we will add Johns Hopkins Bayview Medical Center as a site.

Statistical analyses

The primary outcome variable will be change in accuracy of naming untrained items as measured by the PNT within 1 week after semantic feature analysis ends. The analyses will follow the Intention-to-treat (ITT) principle where participants are analyzed based on the group to which they are randomized regardless of early termination, missing data or errors in randomization detected post hoc. The primary hypothesis is H 0 : mu 1 = mu 2 versus H A : mu 1 ≠ mu 2 , where mu 1 is the mean change in accuracy of naming untrained items between baseline and 1-week post- semantic feature analysis in the tDCS group and mu 2 is the mean change in accuracy of naming untrained items between baseline and 1 week post semantic feature analysis in the sham group. Average Treatment Effect (ATE) will be estimated using linear regression model with change in accuracy of naming untrained items at 1 week as the dependent variable and group assignment (real tDCS versus sham) as the independent variable. ATE is estimated by the coefficient for the group assignment. The analysis will adjust for the covariates included in the stratified randomization.

As a secondary analysis, we will consider non-parametric mixed models for analyses of functional response over time. In particular, let Y ijk = u ik + fk(j) + e ij where Y ij is the the outcome for subject i on occasion j (0, 1, 3, 6) within treatment arm k. (Thus, both i and k are necessary to identify a subject). No covariates are necessary because of the randomization. f k (j) is a functional model we will estimate using quadratic regression splines with knot points at each of the time points. Given there are so few time points, we will not penalize the spline fit. A non-parametric estimate of a treatment effect is given by f 2 –f 1, which can show time-specific treatment effects when evaluated at specific points j. This will also demonstrate the rate (when and if) at which tDCS effects ebb. An overall effect can be estimated by simply taking the integral of f 2 –f 1 (i.e. the functional averaged effect over time). A null hypothesis of zero represents no time averaged effect of the treatment. Given that we will use regression splines, every estimator reduces to standard contrasts of regression parameters, and thus can be implemented in any statistical software package. Statistical analysis of secondary outcome variables will follow a similar approach as the primary outcome variable.

An additional goal of this project is to identify whether neural (functional and structural) biomarkers and linguistic characteristics can predict response to cerebellar stimulation and SFA treatment. This analysis considers moderation of treatment effects by pre-treatment baseline characteristics. The pre-treatment baseline characteristics include the following: Imaging: Structural (lesion volume, site, FA, MD), Functional (Fisher transformed connectivity values ( z scores); Linguistic: (Aphasia Severity score as assessed by WAB-R, Naming severity score assessed by PNT). As in Hypothesis 1, we will consider both a conservative approach, using standard contrasts and median splits on the moderating variables as well as a mixed model functional approach. We will proceed in this order:

• T-test comparing the treatment effect across median splits of the moderating variables performed separately, one at a time.
• One that assumes linearity
• One that assumes non-parametric functions

Data monitoring body

The DSMB consists of scientists in Neurology and Public Health and will monitor safety at least semi-annually and decide if the study should continue or be terminated early. DSMB members include Kyrana Tsapkini, PhD (School of Medicine, Johns Hopkins University), John W. Krakauer, MD (School of Medicine, Johns Hopkins University), and Constantine Frangakis, PhD (Bloomberg School of Public Health, Johns Hopkins University). The study SLP in consultation with the study biostatistician will generate reports semi-annually or more frequently, as determined by the DSMB, which provide statistics on enrollment, participant status, safety data, and data quality information.

Specification of safety parameters

The participant may stop testing or the intervention at any time. tDCS provides a non-invasive method to stimulate the cortex and cerebellum and modulate cortical/cerebellar activity via continuous, weak polarizing electrical current. This study will use the Soterix Medical 1X1 Clinical Trials system to administer tDCS. The Soterix transcranial Direct Current Stimulator Clinical Trials (1x1-CT) system is the most advanced and customizable stimulation for true double-blind control trials. It is powered by four 9-V batteries with an output of 1–2.5 milliamperes (mA). Anodal tDCS (A-tDCS) results in an increase in cortical excitability. Cathodal tDCS results in decrease in cortical excitability. To date, no serious adverse effects of tDCS have been reported in the literature as long as safety guidelines are followed [ 11 , 61 ]. A recent review updated and consolidated the evidence on the safety of tDCS [ 60 ]. This review shows that the use of conventional tDCS protocols in human trials (≤40 min, ≤4 mA) has not produced any reports of a serious adverse effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including participants with stroke. Very minor side effects such as itching, tingling, burning have been reported, as well as temporary headache, sleepiness, dizziness. However, they were generally indistinguishable from those reported by participants receiving sham stimulation. The current study will only administer 2 mA for 25 minutes per treatment session. It is important to note that tDCS does not cause significant heating effects under the electrodes, alter the blood-brain barrier, or induce edema.

Our recent study in chronic post stroke aphasia (20 min, 2mA) in 24 participants did not produce any negative effects associated with tDCS administration beyond mild itching/tingling at the beginning of the treatment session [ 30 ]. A recent large crossover trial in 36 participants with Primary Progressive Aphasia (20 min, 2mA) reported no episodes of intolerability and no serious adverse effects [ 62 ]. On the Wong-Baker FACES Pain Rating Scale, the mean pain rating for tDCS was 2.21 (standard deviation 2.48, range 0–10) and the mean rating for sham was 2.14 (standard deviation 2.13, range 0–10).

Another large, randomized control trial in 74 participants with aphasia reported 8 mild, non-serious adverse events and there were no statistically significant differences between treatment groups for number of adverse events [ 21 ]. 2 participants (6%) in the active tDCS group experienced transient scalp redness/irritation (erythema) compared with none in the sham tDCS group. On the Wong-Baker FACES Pain Rating Scale, most often individuals reported no hurt: 94% (n  =  476) in the active tDCS group vs 86% (n  =  511) in the sham group. The highest pain rating reported was 3 (indicating “hurts even more”), which was reported 4 times by 2 individuals (3%), both in the sham group. Taken together, all available research suggests that prolonged application should not pose a risk of brain damage when applied according to safety guidelines.

Participants may undergo MRI scanning in the present study. The effects of undergoing MR scanning have been extensively studied and there are no risks associated with an MR exam. The patient may, however, be bothered by feelings of confinement (claustrophobia), and by the noise made by the magnet during the procedure. They will be asked to wear earplugs or earphones while in the magnet.

All MRI scans will be reviewed by co-investigator and board-certified neurologist (Dr. Argye Hillis) and any suspicious abnormalities will be referred to a board-certified neuroradiologist. Please note that all of our participants, who will be recruited from the outpatient or stroke clinic, who do not have contraindication for MRI will have had a clinical MRI post-stroke. If unexpected abnormalities ‐ incidental findings ‐ are seen (which is unlikely, as every patient will have had a clinical MRI as part of their evaluation for stroke), the participant will be asked permission to contact the primary care physician about the abnormality and will be offered a timely appointment with a neurologist (Dt. Argye Hillis, co-investigator) if appropriate.

Participants will be carefully screened over the phone prior to being scheduled, to assure that they meet study criteria. tDCS stimulation will be ramped up over the first 15 seconds of stimulation in order to eliminate the sensation of tingling that can occur under the electrodes during the initial moments of tDCS application. The participant may stop testing or the intervention any time. There will be emergency personnel and equipment on hand for safety.

Adverse events will be monitored during the entire visit by the study team. The families will be given telephone numbers of the study team as well. The study physician (Dr. Argye Hillis) and the DSMB will be notified immediately if any adverse events are reported. If a significant safety concern arises, participants may be unblinded in order to address it. The DSMB will determine if the adverse event is a serious adverse event. Adverse events will be monitored until they are resolved or clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness. In the case of any unexpected adverse events involving risks to participants or others that are related/possibly related to the research, a Protocol Event Report will be prepared by the Study Coordinator, the PI will be informed immediately, and the IRB will be contacted within 10 days as per Johns Hopkins Medicine IRB policy; deaths will be reported within 72 hours. Also, as required by IRB policy, any unexpected adverse device effects, potential breaches of confidentiality, unresolved participant complaints will be promptly reported to the IRB. Any other adverse events that do not require prompt reporting will be summarized and reported to the IRB at the time of continuing review.

Summary and concluding remarks

It is our hope that completion of this project will result in better understanding of whether and how cerebellar tDCS coupled with behavioral therapy may help individuals with post stroke aphasia. The cerebellum, which contains more than half of the brain’s neurons and a significant source of input to language as well as motor cortical regions, provides a means by which residual cortical tissue can be stimulated in stroke participants without interference from the lesion itself. However, the effect of cerebellar tDCS combined with behavioral therapy remains incompletely understood. Further, little is known about how factors related to imaging and linguistic characteristics combine to induce treatment responsiveness. We will carry out resting state functional magnetic resonance imaging (rsfMRI), diffusion tensor imaging (DTI), high resolution structural imaging, and detailed linguistic testing before the start of treatment to determine whether these factors can predict response to cerebellar tDCS and/or SFA. This exploratory aim may identify stroke patients who are mostly likely to benefit from cerebellar tDCS and/or SFA. This result may have significant implications for designing a Phase III randomized controlled trial. We will look at the effect size estimates for the primary and secondary outcomes as well as the safety profile to inform the design of the phase III study. Trial results will be submitted to Clinicaltrials.gov no later than one year after the primary completion date. In addition, regardless of outcome, results will be disseminated in peer reviewed journals and contribute to the growing body of literature on the topic of tDCS in post-stroke aphasia rehabilitation.

Supporting information

S1 file. spirit checklist..

https://doi.org/10.1371/journal.pone.0298991.s001

S2 File. Protocol.

https://doi.org/10.1371/journal.pone.0298991.s002

S3 File. Consent form.

https://doi.org/10.1371/journal.pone.0298991.s003

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• 4. Raymer AM, Gonzalez-Rothi LJ, editors. The Oxford handbook of aphasia and language disorders. New York, NY: Oxford University Press; 2018.
• 49. Goodglass H, Kaplan E, Barresi B. BDAE-3: Boston Diagnostic Aphasia Examination–Third Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.

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Stroke expert continues aphasia research in Department of Communication Sciences and Disorders as assistant professor

August 28, 2024  | Erin Bluvas,  [email protected]

With mixed outcomes, stroke survivors have historically all received the same general treatment: stabilize the patient and implement standard rehabilitation procedures (e.g., physical, speech, occupational therapy), continue as needed. But what if scientists and clinicians could customize stroke recovery treatment for each patient? Using new technologies and therapies tailored to the individual?

USC researchers are leading the way in this new approach to post-stroke recovery, and Sigfus Kristinsson is at the forefront. In addition to specializing in the neurophysiology of healthy aging, his work focuses on aphasia – a communication disorder resulting from stroke or injury to the brain that impacts patients’ ability to speak, listen, read and/or write.

It is my hope that my work, both research and community service, will lead to improvements in clinical stroke treatment and ensure every inhabitant of the state access to proper post-stroke care.

“I am passionate about improving the clinical management of aphasia, particularly when it comes to matching individual patients with treatment that will maximize their functional language recovery,” Kristinsson says. “This work considers lesion-based factors as well as personal factors and how these factors interact with the active ingredients in different behavioral treatments.”

“Dr. Kristinsson is an outstanding researcher and teacher,” says Department of Communication Sciences and Disorders chair Jean Neils-Strunjas . “With a background in speech-language pathology from Iceland, he brings diverse perspectives to our clinical training program.”

When Kristinsson arrived at the Arnold School in 2017, he did not expect his stay would last beyond his Ph.D. in Communication Sciences and Disorders program. He was simply following his academic interests, as he had done since he first studied linguistics at the University of Iceland.

“I have always been fascinated by language studies and biology, and one of my undergraduate classes married these two fields,” Kristinsson says. “The topic was simply ‘language in the brain,’ and one of the lectures was on brain damage and subsequent aphasia. I became fascinated with the disorder of aphasia and realized this was the path I wanted to take.”

After completing a master’s in speech-language pathology at the same institution, he gained clinical experience at a rehabilitation center working with patients with neurogenic diseases (e.g., Parkinson’s disease, stroke, traumatic brain injury). He quickly realized, however, that there was much work to be done on the research front to improve treatments offered at clinical practices.

Leaving their quiet, seaside town behind, Kristinsson and his family came to USC so he could conduct the type of research that he wished he had access to as a speech-language pathologist. He wanted to help answer the questions that he and other clinicians face when treating patients.

USC’s location in South Carolina, with its high stroke rates (nearly 17,000 hospitalizations for stroke in 2020), and its well-established research infrastructure makes it the perfect home for stroke and aphasia researchers to collaborate. Kristinsson found that he could make a bigger impact in this environment and decided to stay on as a postdoctoral fellow and then a research assistant professor before becoming an assistant professor in the Department of Communication Sciences and Disorders.

“While it is sad to say that South Carolina, often referred to as ‘the buckle of the stroke belt,’ has an unusually high incidence of stroke, this fact means that USC is a leading authority in stroke research,” he says. “It is my hope that my work, both research and community service, will lead to improvements in clinical stroke treatment and ensure every inhabitant of the state access to proper post-stroke care.”  

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• Volume 2014, Issue
• Broca aphasia
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• Takashi Watari 1 ,
• Taro Shimizu 1 ,
• Yasuharu Tokuda 2
• 1 Department of Internal Medicine , Tokyo Joto Hospital , Tokyo , Japan
• 2 Japan Community Healthcare Organization , Tokyo , Japan
• Correspondence to Dr Taro Shimizu, shimizutaro7{at}gmail.com

https://doi.org/10.1136/bcr-2014-208214

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Description

An 80-year-old Japanese woman presented with sudden onset of speech disturbance and confusion. She was riding a bicycle when she suddenly felt unwell and subsequently noticed she could not find words to express her thoughts. A pedestrian found her sitting on the ground, at a loss for words and looking confused. She was brought to the emergency department for evaluation. On examination, she was alert, but looked very anxious, frustrated and confused. She was not oriented to time, place and person. She spoke hesitantly and non-fluently, she seemed not to be able to find words to respond (speaking and writing) to the physician's questions. She also showed impairment in repetition and comprehension to questions with complex syntax. The rest of the neurological examination was normal. Laboratory studies showed high cholesterol and elevated glycated haemoglobin of 8.2.

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Diffusion-weighted MRI showing ischaemic findings involving the Broca area.

Three-dimensional MR angiography showing a signal loss (arrows) at the distal point of the left middle cerebral artery.

Differential diagnosis of Broca aphasia

Ischaemic disease

Cerebral infarction

Transient ischaemic attack

Haemorrhage

 Intracerebral haemorrhage

 Traumatic injury

 Subdural haematoma

 Subarachnoid haemorrhage

 Herpes encephalitis

 West Nile encephalitis

 Bacterial infection/abscess

 Fungal abscess

 Prion disease

 Toxoplasmosis

 Lyme disease

Degeneration

 Alzheimer’s disease

 Primary progressive aphasia

 Amyotrophic lateral sclerosis

Demyelination

 Multiple sclerosis

 Acute disseminated encephalomyelitis

 Primary brain tumour

 Brain metastases

 Sarcoidosis

 Conversion disorder

 Wernicke’s encephalopathy

Learning points

Broca aphasia should be suspected when a patient has difficulty in repetition and naming, and if dysfluency or inaccuracy of expression of speech and writing are detected.

The diagnosis is sometimes difficult because of the limited manifestation of symptoms.

• Daroff RB , et al
• Ochfeld E ,
• Newhart M ,
• Molitoris J , et al

Contributors TW wrote the manuscript. TS and YT revised the manuscript.

Competing interests None.

Patient consent Obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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Diagnosing and managing post-stroke aphasia

Shannon m. sheppard.

1. Department of Communication Sciences and Disorder, Chapman University, Irvine, CA, USA

2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Rajani Sebastian

3. Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Introduction:

Aphasia is a debilitating language disorder and even mild forms of aphasia can negatively affect functional outcomes, mood, quality of life, social participation, and the ability to return to work. Language deficits after post-stroke aphasia are heterogeneous.

Areas covered:

The first part of this manuscript reviews the traditional syndrome-based classification approach as well as recent advances in aphasia classification that incorporate automatic speech recognition for aphasia classification. The second part of this manuscript reviews the behavioral approaches to aphasia treatment and recent advances such as non-invasive brain stimulation techniques and pharmacotherapy options to augment the effectiveness of behavioral therapy.

Expert opinion:

Aphasia diagnosis has largely evolved beyond the traditional approach of classifying patients into specific syndromes and instead focuses on individualized patient profiles. In the future there is a great need for more large scale randomized, double-blind, placebo-controlled clinical trials of behavioral treatments, non-invasive brain stimulation and medications to boost aphasia recovery.

1. Introduction

Approximately 1/3 of people who have a stroke will be diagnosed with aphasia ( 1 , 2 ), which is an acquired language disorder where patients experience impairments of various aspects of their language system (i.e., phonological, morphological, semantic, syntactic, and/or pragmatic). Aphasia is not a singular disorder, and can look very different from patient to patient. Even within the same patient, symptoms associated with aphasia can change quite drastically, particularly within the first few weeks and months following a stroke. The specific profile of language impairments depends on many factors including the size and location of stroke, health background (e.g., diabetes, history of prior stroke), access to quality medical care, how quickly medical treatment was received after stroke, and the time since stroke. Furthermore, even the mildest forms of aphasia can have detrimental effects on patient’s lives including loss of employment, social isolation, depression, and lower quality of life ( 3 – 6 ).

1.1. World Health Organization International Classification of Functioning, Disability, and Health (WHO ICF)

The WHO ICF is a framework for describing and organizing information on functioning and disability ( 7 ). The ICF stresses health and functioning rather than disability. The ICF distinguishes between impairments in body function or structure, activity limitations (difficulties an individual may have in executing tasks/actions), and participation restrictions (difficulties participating in life situations). It is important to consider the ICF when making diagnostic and treatment decisions for individuals with stroke-based aphasia ( 8 – 10 ).

2. Aphasia diagnostics

2.1. classification of aphasia.

Historically aphasiologists developed several different methods of classifying different subtypes of aphasia. The most popular system is the Boston classification system, which was developed in the 1960s by Norman Geschwind, Frank Benson, Harold Goodglass, and Edith Kaplan, who updated classical descriptions of aphasia subtypes. The Boston neoclassical classification system includes eight aphasia subtypes: 1) Broca’s, 2) Transcortical Motor, 3) Global, 4) Mixed Transcortical (aka Isolation aphasia), 5) Wernicke’s, 6) Transcortical Sensory, 7) Conduction, and 8) Anomic. Each of these subtypes is characterized by a specific profile of symptoms based on fluency of verbal expression (i.e., fluent vs. non-fluent speech), language comprehension skills, and repetition abilities (see Figure 1 ). It should be noted that most people with aphasia will have some level of difficulty with comprehension, spontaneous speech, reading, and writing. Typically, aphasia assessment is focused on identifying areas with the most profound impairment. These classical profiles are sometimes termed cortical aphasias, and are based on an understanding of classic left hemisphere cortical language regions such as Broca’s area and Wernicke’s area. Each subtype was theorized to be associated with damage to particular cortical regions, with some potential extension into subcortical regions, although the reliability of these predictions is debated in literature ( 11 , 12 ). For example, Kasselimis and colleagues ( 11 ) classified 65 patients using the Boston classification system and also obtained neuroimaging in each patient. Lesions were only located in the regions predicted by the Boston system in 36.5% of cases. On the other hand, Yourganov and colleagues ( 12 ) found a high correlation between aphasia syndrome and predicted lesion location.

Aphasia Classification. The eight aphasia subtypes identified by the Boston neoclassical system are defined based on measures of fluency, comprehension, and repetition. Note the figure depicts lesions that are often associated with each subtype of aphasia, however there is inherent heterogeneity in stroke patients and a patient may present with a specific subtype of aphasia even if their lesion does not match the area depicted in this figure.

2.1.1. Boston aphasia syndromes

2.1.1.1. non-fluent aphasias:, 2.1.1.1.1. broca’s aphasia.

Broca’s aphasia is often termed “expressive aphasia” and is characterized by halting, effortful, non-fluent speech that has reduced phrase length, impaired melody, and diminished words per minute. Language output (both written and spoken) is agrammatic, meaning it consists mostly of content words with few, if any, function words. Repetition is typically impaired. Comprehension of single words and syntactically simpler sentences (e.g., active sentences) are often spared; comprehension of syntactically complex sentences (e.g., passive sentences) is often impaired. Individuals with Broca’s aphasia have a range of reading and writing skills. While Broca’s aphasia is associated with damage to Broca’s area, in chronic Broca’s aphasia the damage often extends into surrounding frontal lobe areas, insula, and sometimes subcortical structures ( 13 , 14 ). Because Broca’s area is located near the motor strip, it is also often accompanied by right hemiplegia.

2.1.1.1.2. Transcortical motor aphasia

Transcortical motor aphasia presents very similarly to Broca’s aphasia, except repetition of words and sentences is relatively preserved. More fluent speech is observed when a patient is repeating words, phrases, or sentences, compared to their spontaneous speech output. Patients have great difficulty initiating speech, and often present with echolalia ( 15 ). Transcortical motor aphasia is associated with lesions just anterior or superior to Broca’s area in the medial frontal cortex and the presupplementary motor area ( 15 – 17 ).

2.1.1.1.3. Global aphasia

Global aphasia is the most severe subtype of aphasia, as patients experience difficulties with all aspects of language. However, other modalities like facial expressions and gestures can be used to communicate basic needs or feelings ( 18 ). Comprehension is significantly impaired even at the single word level, and spoken output is severely limited. Spontaneous speech, naming, and repetition are often constrained to recurring utterances (e.g., “nuh, nuh, nuh”; parts of speech “I want to” etc.). Global aphasia is associated with large left hemisphere lesions affecting Broca’s area and Wernicke’s area ( 14 , 19 ).

2.1.1.1.4. Mixed transcortical aphasia (aka isolation aphasia)

Mixed transcortical aphasia is similar to global aphasia, except repetition skills are spared. Lesions are typically large and surround Broca’s and Wernicke’s area (watershed regions). Broca’s and Wernicke’s areas remain intact, but language recognition and production appear to be isolated from intentions generated elsewhere in the brain ( 20 ).

2.1.1.2. Fluent aphasias:

2.1.1.2.1. wernicke’s aphasia.

Wernicke’s aphasia is often called “receptive aphasia” and is characterized by fluent speech, paired with significant impairments of comprehension, naming, and repetition. Speech is fluent so the rhythm of speech is maintained, but it typically consists of jargon and is empty of meaning with a mix of sentence constructions (paragrammatism. Language output contains many paraphasias including semantic paraphasia (e.g., saying “train” for the target word “bus”) and neologisms (nonwords like “fluffertump”). Error awareness is often poor due to limited auditory comprehension, and this makes communication less effective compared to patients with Broca’s aphasia. Reading and writing are frequently significantly impaired. Wernicke’s aphasia is typically associated with damage to Wernicke’s area along with neighboring temporal and parietal regions ( 21 ).

2.1.1.2.2. Transcortical sensory aphasia

Transcortical sensory aphasia is similar to Wernicke’s aphasia, except repetition skills are intact. This type of aphasia is associated with lesions surrounding Wernicke’s area, between the areas of the brain fed by the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) ( 18 , 22 ).

2.1.1.2.3. Conduction aphasia

Patients with conduction aphasia have fluent speech with phonemic distortions, relatively good comprehension, and mild to moderate naming deficits. Repetition skills are disproportionally impaired relative to comprehension and expression. Conduction aphasia was classically associated with damage to left arcuate fasciculus, which is a white matter tract connecting Wernicke’s and Broca’s areas ( 18 ). However, more recent research implicates temporoparietal regions ( 18 , 23 ).

2.1.1.2.4. Anomic aphasia

Anomic aphasia is the least severe aphasia syndrome, and is characterized by marked difficulty with naming but no other profound comprehensive and expressive deficits. Speech is fluent with the exception of intermittent pauses and hesitations resulting from word finding difficulties. Lesions can be located anywhere in the left hemisphere language network, including subcortical regions ( 14 , 16 ).

2.1.2. Other types of aphasia

2.1.2.1. subcortical aphasia.

More recently subcortical aphasias have also been identified, where damage is confined to subcortical areas alone. In the review of eight neoclassic syndromes it was noted that subcortical damage may accompany cortical damage. However, in subcortical aphasias, only subcortical damage is present. Subcortical aphasias are often divided into two groups: thalamic aphasia, and striato-capsular aphasia. Thalamic aphasia is characterized by severe anomia, presence of verbal paraphasias, reduced spontaneous verbal output, with variable comprehension skills ( 24 – 26 ). Variability in comprehension findings across studies of patients with thalamic aphasia may be due to the involvement of specific thalamic nuclei or subnuclei ( 25 ). Striato-capsular aphasia is associated with lesions in basal ganglia (head of caudate nucleus, putamen, anterior limb of the internal capsule). Researchers have attempted to define clinical syndromes associated with specific areas of basal ganglia damage ( 27 , 28 ), but no strong clinical consensus has been reached ( 16 , 29 ). Mounting evidence ( 29 – 31 ) suggests that basal ganglia lesions are associated with hypoperfusion in cortical areas, which in turn explains symptoms of aphasia.

2.1.2.2. Crossed aphasia

Crossed aphasia is the term used to describe aphasia that results from damage to the hemisphere non-dominant for language (in most individuals this is the right hemisphere). Crossed aphasia is rare, but appears to result from a small minority of people who have reversed asymmetry of language functions in the right hemisphere even when they are right-handed. Crossed aphasia can be a mirror image of the left hemisphere profile so each of the neoclassical syndromes discussed above could potentially occur ( 32 , 33 ). However, in about 40% of cases anomalous profiles also occur where the extent and site of lesion doesn’t map well to the associated symptoms ( 33 ).

2.1.2.3. Alexia and agraphia

In addition to broad language comprehension and production deficits, stroke can also cause reading and writing deficits. Alexia refers to reading deficits and agraphia refers to writing deficits. In cases of pure alexia, patients demonstrate reading impairments in the absence of any other deficits ( 34 , 35 ). Pure alexia is associated with simultaneous damage to 1) left occipital cortex, which causes right homonymous hemianopsia where visual information is initially processed in the right occipital cortex, and 2) splenium of the corpus callosum, which then prevents visual information in the right hemisphere from crossing over to the left hemisphere, where language is processed ( 36 ). Pure agraphia refers to cases where writing impairments are present in the absence of other difficulties ( 35 ). Spelling deficits are associated with damage to left inferior parietal cortex and left occipitotemporal cortex ( 37 ).

2.1.3. Classification considerations

2.1.3.1. recent advances in aphasia classification.

There is no perfect aphasia classification system. It is relatively common for a patient’s language impairment profile to be unclassifiable because they do not fit neatly within any of the well-defined neoclassical aphasia syndromes. Even when patients do fit within a specific profile, they may differ quite significantly from other patients who have the same syndrome classification. For example, one patient with Broca’s aphasia may also have mild-moderate reading comprehension deficits, while another does not. Additionally, a patient’s classification may change depending on the specific test battery that was used. Because of these concerns, researchers have continued to develop new approaches to aphasia classification. For example, several researchers have investigated the utility of machine learning approaches to reduce uncertainties in aphasia classification ( 38 – 40 ). Alternatively, some researchers advocate for moving away from a syndrome-based approach and instead focusing on a more individualized approach which aims to identify the precise points of impairment in language processing, such as semantic, phonological, or syntactic disorders ( 11 , 41 , 42 ).

2.1.3.2. Classification - time since stroke:

Another aspect of aphasia classification to consider is the time since stroke. Patients undergo a period of spontaneous recovery immediately following a stroke, where they may experience drastic improvements in language and cognitive functioning. Therefore, a patient may look very different if tested at the acute stage (within ~ 1 week of stroke) compared to the chronic stage (often defined as more than six months or one-year post-stroke). Unsurprisingly, there is significant variability across patients in terms of aphasia recovery in the months following a stroke ( 43 ). Because of the natural recovery and functional reorganization, a patient’s aphasia classification is likely to evolve rapidly over the first few days, weeks, and months following a stroke. For example, patients diagnosed with acute Broca’s aphasia may recover and be later diagnosed as having chronic anomic aphasia ( 44 , 45 ). Acute aphasia may resolve completely by the chronic stage of recovery ( 44 ). Typically, language impairments will be most severe at the acute stage, with the greatest period of recovery occurring within the first three months ( 46 ). However, some patients do experience decline, which can be attributed to several possible factors including the onset of vascular dementia or a lack of speech and language therapy ( 47 , 48 ).

2.1.4. Clinical terminology for classification

Depending on the clinical setting, speech language pathologists are often not expected to classify syndromes according to the Boston classification system. Some other common classifications include distinguishing between nonfluent and fluent aphasia. Patients may also be described as having receptive aphasia vs. expressive aphasia. Receptive aphasia refers to difficulty with language (auditory or written) comprehension, while expressive aphasia refers to difficulty with language production. Sometimes speech language pathologists will describe the relative severity of receptive and/or expressive deficits as either mild, moderate, or severe. For example, a patient may be described as having aphasia with mild receptive deficits and moderate-severe expressive deficits. However, this isn’t best practice as classifying receptive vs. expressive deficits does not provide any information about the type of receptive or expressive deficits. For example, we would expect all patients with aphasia to have expressive language deficits on some level (e.g., word finding difficulty, non-fluent speech, etc.). Thus, stating a patient has mild expressive deficits does not provide information about whether the deficits are due to word finding difficulties, or non-fluent speech or another type of deficit.

2.2. Diagnostic testing

Conducting a comprehensive assessment is vital to forming meaningful and feasible treatment goals and activities. Moreover, in light of the WHO ICF, aphasia assessment must surpass simply identifying deficits and instead aim to gain a full understanding of how deficits have restricted the patient’s daily life and social activities. It is important to first obtain an accurate case history including background information such as occupation, language and cultural background, and medical history. A comprehensive aphasia assessment includes each component of language (e.g., syntax, semantics), in every modality (comprehending and expressing spoken language, written language, and gestures). Fluency and quality of spontaneous speech should be assessed using tasks like picture description, and asking open ended questions. Naming can be assessed using confrontation naming tasks. Auditory comprehension should be assessed at several levels including single words (nouns and verbs), sentences (syntactically simple and complex), and multi-step commands. It is also important to investigate the reliability of yes/no responses to ascertain if the patient has more reliable yes/no responses with gestures vs. speech. Repetition of words, phrases, and sentences should also be assessed. It is critical to consider repetition skills relative to other language skills.

The Boston Diagnostic Aphasia Examination, 3 rd edition (BDAE) ( 49 ), and the Western Aphasia Battery – Revised (WAB-R) ( 50 ) are the most common comprehensive aphasia assessments. The BDAE assesses spontaneous speech (conversational and narrative), auditory comprehension, repetition, reading, and writing. The BDAE has a short form that takes about 30-45 minutes to complete, and an extended standard form. The BDAE also includes the Boston Naming Test (BNT), which is a widely used measure of confrontation object naming. Similarly, the WAB-R assesses spoken language production and comprehension, reading and writing, praxis, and constructional and visuospatial skills. Both the BDAE and the WAB-R allow clinicians to classify patients into syndromes. However, as discussed in the “ Recent Advances in Aphasia Classification” section above, a growing number of researchers and clinicians are moving away from the syndrome-based approach. Instead there is an emphasis on identifying specific deficits rather than trying to fit individual patients into a “syndrome” box.

In line with this new way of thinking, the Comprehensive Aphasia Test (CAT) ( 51 ) is a comprehensive assessment that does not assign patients to syndrome classifications. The CAT consists of an initial screening for cognitive deficits that may impact performance on the aphasia battery, a comprehensive language performance assessment (the main body of the test), and a disability questionnaire. The disability questionnaire asks the individual with aphasia to assess their degree of disability in all four language modalities, and is designed to ascertain the emotional consequences and impact that language difficulties have on their daily life.

It is important to follow up the comprehensive battery with tests designed to probe further into specific linguistic and/or cognitive deficits. For example, the Psycholinguistic Assessment of Language Processing in Aphasia (PALPA ( 52 )), has 60 assessments that a clinician can select from depending on the specific area they want to probe in further detail. The Northwestern Assessment of Verbs and Sentences (NAVS) ( 53 ) can be used to examine the comprehension and production of action verbs and several types of canonical and noncanonical sentences, as well as the production of verb argument structure in sentence contexts. If clinicians suspect patients have syntactic deficits, or difficulties with verbs, the NAVS can offer a thorough assessment of different verb- and sentence-types. It is also important to diagnose nonlinguistic cognitive deficits (e.g., difficulties with memory, attention, executive functioning), as the presence and severity of domain-general cognitive deficits will impact treatment decisions.

Another important area to probe is functional communication. The ASHA Functional Assessment of Communication Skills for Adults (ASHA-FACS) ( 54 ) can be used to evaluate functional communication in four areas: 1) social communication, 2) communication of basic needs, 3) reading, writing and number concepts, 4) and daily planning. Some other tests of functional communication include The Amsterdam-Nijmegen Everyday Language Test (ANELT) ( 55 ), the Scenario Test ( 56 ) and the Communicative Effective Index (CETI) ( 57 ).

Activity limitations, poor functional communication, and changes to social relationships can all negatively impact quality of life in individuals with aphasia ( 58 – 60 ). It is important to assess quality of life in aphasia because there is a high prevalence of poor quality of life in this group ( 61 ). The Stroke and Aphasia Quality of Life Scale (SAQOL) ( 62 ) is an interview-based self-report scale that can be used to assess quality of life in aphasia.

3. Aphasia treatment

3.1. behavioral approaches to treatment.

Aphasia therapy varies across several dimensions and depends upon many factors including patient goals, specific impairments, treatment setting, and delivery model. Clinicians can take a restorative approach, where the goal is to improve deficits, or a compensatory approach, where the goal is to compensate for deficits that cannot be restored. With regards to the WHO ICF ( 7 ), restorative approaches focus on body functions/structures while compensatory approaches focus on activities/participation. Another distinction can be made between impairment-based approaches, which focus on training specific linguistic deficits, and functional approaches, which emphasize real-life treatment goals that will have value outside of the therapy room. The impairment-based approach follows a medical model, whereas a functional approach follows a patient-centered social model. Clinicians may choose to use a combined impairment-based and functional approach, which is likely to have the most positive outcome for individuals with aphasia ( 63 ).

3.1.1. Review of treatment options

Many behavioral approaches to aphasia treatment exist, and here we provide a brief overview of a portion of the numerous available options. First, community support approaches aim to help individuals with aphasia successfully participate in their community. For example, the Life Participation Approach to Aphasia (LPAA) is a general philosophy, rather than a service delivery model, that focuses on re-engagement in life. LPAA aims to empower individuals with aphasia to participate in their recovery and fully engage in daily activities of their choice. A strong support system is vital to this approach ( 64 ). Community aphasia groups can have a support model where the main goal is to provide social support to participants, or a therapy model, where the primary goal is to provide speech language therapy services. It is vital that clinicians keep the needs of each individual participant in mind. People with severe aphasia will likely require increased structure to help them get the most out of the group ( 65 ), while people with mild aphasia are more at risk for feeling like an outsider ( 66 ). Community aphasia groups offer an excellent opportunity for combating the social isolation that has devastating consequences on people with aphasia ( 65 , 67 , 68 ).

For individual therapy sessions, clinicians can choose from many different approaches depending on the goals and characteristics of their individual clients. One unique approach is Melodic Intonation Therapy (MIT). Because right hemisphere functions like singing and knowledge of melody and rhythm are often relative strengths in individuals with non-fluent aphasia, MIT capitalizes on these strengths to improve language expression. Ideal candidates for MIT have: nonfluent speech with the ability to produce some intelligible words while singing familiar songs, relatively good comprehension, impaired repetition, a good attention span and strong motivation ( 69 ). MIT consists of several levels from singing simple phrases to speaking phrases with five or more syllables ( 69 – 71 ). Another popular approach for expressive language deficits is Constraint-Induced Language Therapy (CILT). CILT encourages individuals with aphasia to use spoken language, and discourages the use of compensatory strategies such as writing and using gestures in place of spoken language ( 72 ). A hallmark of CILT is its intensive approach requiring massed practice (e.g., 3-hour therapy sessions at least five days a week for two weeks).

Several therapy options are available for patients with word finding deficits. Semantic feature analysis (SFA) trains patients to produce semantic information when they are struggling to produce a specific word. It is theorized to improve word retrieval by increasing semantic network activation ( 73 , 74 ). If a client cannot produce a target word they would be prompted to answer questions about what it is used for, what it looks like, where it is found etc. Phonological Components Analysis (PCA) treatment was modeled after the SFA approach, and asks participants to identify five phonological components related to the target word as a method for treating word finding deficits ( 75 ). Another word retrieval treatment is Verb Network Strengthening Treatment (VNeST), which focuses on promoting word retrieval at the phrase- and sentence-level. Similar to SFA, VNeST is also designed to promote semantic network activation. VNeST aims to strengthen associations between verbs and related agents and patients ( 76 – 78 ). The protocol involves giving the client an appropriate transitive verb (e.g., “cook”), and instructing them to produce related agents and patients (e.g., “chef cooks dinner”). Research demonstrates that VNeST leads to improved single word retrieval, as well as word retrieval in sentences ( 76 – 78 ).

Treatment of Underlying Forms (TUF) is a treatment approach that also focuses on sentence-level tasks. TUF is used to treat the comprehension and expression of sentences, and is designed for patients with mild – moderately severe agrammatic Broca’s aphasia ( 79 ). Patients who will most likely benefit from TUF have better word-level than sentence-level comprehension, more difficulty comprehending semantically reversible sentences than non-reversible sentences, and more difficulty comprehending non-canonical than canonical sentences. They also have more difficulty producing verbs than nouns, and more difficulty producing syntactically complex vs. simple sentences. Research indicates TUF promotes improvement on trained syntactic structures as well as generalization to untrained structures ( 79 – 81 ).

3.1.2. Treatment settings

Aphasia treatment can occur in many different settings, and will often look quite different from one setting to the next. An aphasia assessment typically occurs during the initial hospital stay in the days following a stroke. Patients are subsequently discharged to an acute rehabilitation unit, a nursing home or skilled nursing facility, or back to their home. Treatment may begin during the acute stay in the hospital, but it is common for patients to be transferred to a lower level of care relatively quickly, and therefore treatment may not begin until after they have been transferred. Aphasia treatment centers offer another unique treatment option. Aphasia centers are dedicated to providing resources and therapy specifically tailored for individuals with aphasia, and offer activities designed to increase participation in line with the WHO ICF model ( 82 , 83 ).

Recently, given the global COVID-19 pandemic, an emphasis has been placed on providing clients with therapy via telepractice. Telepractice has the added benefit of allowing speech language pathologists to reach patients who are isolated either by geography, or by physical limitations. Research shows that language therapy provided via telepractice can benefit patients ( 84 ) and can also be successfully used to provide communication partner training ( 85 ). In addition to telepractice techniques, research has shown promising results for computer-based and tablet-based therapy ( 86 – 88 ). Various computer programs have been developed for aphasia rehabilitation. These include communication aids such as Sentence-Shaper (Psycholinguistic Technologies, Jenkintown, PA) ( 89 ), Lingraphica (Lingraphica Inc., Princeton, NJ), and Touchspeak (Touchspeak, London, England). In addition, there are several self-delivered tablet or desktop based aphasia therapy. These include Sentactics ( 90 ), ORLA-VT (Oral Reading for Language in Aphasia ( 91 ), and Constant Therapy ( 87 ). Self-delivered language therapy can also be used to increase treatment intensity, as patients can participate in therapy tasks at home between formal language therapy sessions. Advances in technology also means that therapy can be conducted within a virtual environment. For example, EVA Park is a multi-user virtual world that will likely be available in the near future where individuals with aphasia can interact with their speech pathologist, and other individuals with aphasia ( 92 – 94 ). They create their own avatar and can explore EVA Park while practicing their language and communication. The COVID-19 pandemic has resulted in a push for creating more diagnostic and therapy materials, which will be beneficial to clinicians and patients even after the pandemic has resolved.

Research indicates that the benefits of neuroplasticity can extend well beyond the first year following a stroke, and therefore therapy-induced recovery can be seen even in individuals who have had chronic aphasia for several years ( 95 – 97 ). Therefore, even in cases where insurance has limited the total number of formal language therapy sessions, the growing virtual options may allow individuals with aphasia to access the resources they sorely need.

3.2. Pharmacological treatment

Pharmacotherapy has been used in the treatment of post-stroke aphasia for several decades now; however, there has been a recent emphasis on augmenting language skills in aphasia with pharmacological agents already approved for the treatment of other neurological and psychiatric disorders ( 98 , 99 ). Pharmacological interventions for aphasia are mainly designed to strengthen networks subserving language and language-related cognitive functions such as attention and memory ( 100 ). The theoretical rationale for pharmacological intervention in aphasia is based on the notion that re-establishing the activity of specific neurotransmitters that are dysfunctional, but not irretrievably damaged, brain regions may strengthen neural activity in networks mediating attention, word learning, and memory ( 101 , 102 ). Pharmacological agents are increasingly used alone and in combination with speech and language therapy to boost language recovery. Please see ( 98 , 99 ) for reviews on this topic.

Catecholaminergic, Cholinergic, Nootropic and Serotonergic drugs are the main classes of drugs investigated for the treatment of aphasia . Bromocriptine , a Catecholaminergic drug has been the most studied drug for patients with aphasia. Positive effects of Bromocriptine have been seen mainly in non-fluent chronic aphasias ( 103 – 106 ), but these studies were mostly case studies or open label trials. In addition, language gains were only specific to certain language subtests, but were not effective in moderate to severe cases. Randomized, double-blind controlled trials failed to replicate positive results of Bromocriptine ( 104 , 107 , 108 ). It should be noted that the use of bromocriptine is no longer recommended due to high frequency of contraindications (> 40 %) ( 109 ) and the increased risk of inducing off-target effects such as valvular heart disease ( 110 ) and painful hemidystonia in aphasic persons with hemiparesis ( 111 ).

Donepezil is the mostly commonly investigated cholinergic drug in the treatment of aphasia. Cholinergic agents specifically acetylcholinesterase inhibitors such as Donepezil, are widely used in the treatment of Alzheimer’s disease. Donepezil has been reported to result in improvement of spontaneous speech, naming and comprehension in chronic post-stroke aphasia in randomized trials, open label trials, and case studies ( 112 – 115 ). It also has a well-tolerated safety profile. Piracetam, the nootropic agent is another drug that is commonly used in the treatment of aphasia ( 101 , 116 , 117 ). However, studies assessing the efficacy of piracetam on post-stroke aphasia have produced inconsistent results ( 99 ). In addition, piracetam acts on the initial phase of stroke ( 118 , 119 ), but its beneficial effects disappear in the chronic stage ( 116 ). Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Like Piracetam, the initial enthusiasm to evaluate the potential efficacy of memantine in post-stroke aphasia was prompted by the beneficial effects obtained with this drug in language and communication among patients with Alzheimer’s disease ( 100 ). Two studies showed that memantine alone and combined with constraint-induced aphasia therapy (CIAT) improved aphasia severity ( 120 , 121 ).

Interest in serotonin selective reuptake inhibitors (SSRIs) after stroke has been renewed by a better knowledge of post-stroke depression. The issue of depression is important to consider in the treatment of post-stroke aphasia. There is a high rate of post-stroke depression ranging from 30-60% of stroke survivors ( 122 , 123 ). Furthermore, untreated depression can impede not only language performance, but also motivation to participate in SLT ( 124 , 125 ). The SSRI fluvoxamine has showed significant improvements in naming, reduced perseverations, and mood after a 4-week treatment compared to controls ( 126 ). A recent study showed that patients with damage to left posterior superior temporal gyrus and/or superior longitudinal fasciculus/arcuate fasciculus showed better naming outcome if they took SSRIs for 3 months after stroke [47].

It is important to keep in mind that drugs prescribed for the treatment of other diseases or stroke complications (e.g. epilepsy) can interfere with aphasia recovery [96, 97]. For example, although seizures are common following stroke, anticonvulsant drugs such as the use of topiramate and zonisamide should not be recommended as first-choice medications because they can impair attention, psychomotor speed, short-term and working memories, as well as expressive language ( 127 , 128 ).

3.3. Non-invasive brain stimulation

There has been an increasing interest in the use of non-invasive brain stimulation techniques (NIBS) such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) to enhance recovery of aphasia. Please see ( 129 ), ( 130 ) for detailed reviews. This interest stems from the growing body of evidence indicating that non-invasive brain stimulation techniques can induce long-lasting changes in neural excitability resulting in functional reorganization and improved speech and language performance.

3.3.1. Transcranial direct current stimulation (tDCS)

tDCS is usually administered via saline-soaked surface sponge electrodes attached to the scalp and connected to a direct current stimulator with low intensities (1-2 mA). tDCS can increase or decrease cortical excitability due to a shift of the resting membrane potential of the nerve cells in the brain ( 131 ). Anodal stimulation typically increases cortical excitability, whereas cathodal stimulation lowers cortical excitability. The majority of the tDCS studies in aphasia have focused on excitatory, anodal stimulation applied to the left hemisphere perilesional or ipsilesional regions ( 132 – 140 ). Other tDCS studies have focused on inhibitory, cathodal stimulation to the healthy right hemisphere regions to inhibit cross-hemisphere inhibition, allowing greater activation of the lesioned left hemisphere ( 141 – 143 ). A few studies have focused on bihemispheric tDCS, aiming at concomitantly increasing left hemisphere excitability with anodal stimulation and decreasing right hemisphere excitability with cathodal stimulation ( 144 – 146 ). The newest approach to neuromodulation for aphasia is targeting the right cerebellum ( 147 , 148 ), a region that is structurally and functionally connected to the left hemisphere language region. This is particularly well suited for patients who have large left hemisphere stroke where it may be difficult to find viable tissue to stimulate in the left hemisphere.

The results of tDCS studies in aphasia have been mostly positive indicating that tDCS can augment aphasia therapy; however, the majority of the studies are small. So far, only two tDCS studies have included more than 50 patients ( 135 , 149 ). The largest clinical trial of tDCS to augment naming treatment for post stroke aphasia was done by Fridriksson and colleagues ( 135 ) using a randomized, double-blind, sham-controlled design. In this study of 74 chronic stroke patients with aphasia, tDCS electrode placement was individualized for each participant based on the area of greatest activation in the left hemisphere during spoken naming pre-treatment functional magnetic resonance imaging (fMRI). Patients received 15 sessions of tDCS combined with computerized aphasia treatment. tDCS was associated with significantly greater change in number of correctly naming pictured objects compared to sham. Spielmann and colleagues ( 149 ) studied the effect of tDCS on naming outcome in 58 patients with subacute (first three months) post stroke aphasia. Using a randomized, double-blind, sham-controlled design, participants received anodal stimulation to the left inferior frontal gyrus combined with naming treatment for 10 days. The study by Spielmann and colleagues failed to show significant effects of tDCS. The authors hypothesized that an effect of tDCS might be difficult to achieve in the subacute phase, as spontaneous recovery is rather high in this phase compared with the relatively stable chronic phase.

3.3.2. Transcranial Magnetic Stimulation (TMS)

TMS is a non-invasive brain stimulation method that induces changes in neuronal firing via electromagnetic induction. Typically, a brief and strong current is delivered through a stimulation coil over the scalp, which induces a perpendicular time-varying magnetic field that penetrates the scalp without attenuation. This magnetic field will induce a weak and short-lived current at the site of stimulation ( 150 ). Repetitive TMS (rTMS) can be delivered at both high frequency (excitatory) and low frequency (inhibitory).

The majority of TMS studies have applied low-frequency rTMS to right hemisphere regions to inhibit right hemisphere activation during language-related tasks and to encourage perilesional left hemisphere activation ( 151 – 156 ). Other studies have focused on facilitating activation of residual left hemisphere regions ( 157 ) or facilitating activation of right hemisphere regions ( 155 ) via high frequency rTMS. Theta burst stimulation (TBS) is another type of rTMS protocol that has recently gained interest. TBS protocols induce robust, long-lasting changes in activation in much shorter time periods than are necessary for traditional rTMS ( 158 , 159 ).

Both low-frequency and high-frequency rTMS have been beneficial in improving language outcomes for subacute and chronic aphasia. However, the majority of studies are small. There are only a few relatively large randomized sham-controlled trials ( 154 , 160 ). Hu et al. showed that that both high and low frequency rTMS of the right IFG can be effective in chronic post stroke aphasia. Ren et al., results indicate that inhibitory low frequency rTMS of right IFG and right STG both lead to language improvements in subacute aphasia, demonstrating that targets beyond right IFG can be effective.

Both tDCS and TMS are promising tools for the treatment of aphasia. However, it is unclear which approach is beneficial for improving language skills. There is an increased interest in using tDCS compared to TMS because tDCS is less expensive and portable; and does not carry a risk of inducing seizures ( 161 , 162 ). In addition, tDCS is more easily paired with simultaneous speech therapy, making it more amenable to widespread clinical use.

3.3. Reperfusion therapies

Over the last two decades, various therapeutic approaches have been developed for treating acute ischemic stroke. Reperfusion therapies are medical treatments in acute stroke that restore blood flow either by surgical removal of a blood clot or with medications that dissolve clots. Reperfusion therapies, particularly intravenous thrombolysis with recombinant tissue plasminogen activator (rTPA), have been shown to be effective in improving language after acute ischemic stroke in the left hemisphere ( 163 – 166 ). For example, a recent study in patients with ischemic stroke showed significantly higher percentage of resolved aphasia in patients treated with rTPA compared to the non-treated group, and a higher percentage of global aphasia was observed in the non-treated group compared to treated patients ( 167 ). However, many stroke patients do not receive this treatment due to the narrow treatment window (<4.5 h) ( 168 ).

Carotid stenting, with or without angioplasty, is a common procedure to restore blood flow, prevent stroke, and/or improve tissue function. For example, Hillis and colleagues have shown that acute aphasia resolved after left carotid stenting associated with reperfusion of the language cortex ( 169 ). Increasing blood pressure is another approach that investigators have used to improve stroke symptoms. In a series of studies, Hillis et al. showed that restoring blood flow to specific cortical regions in the left hemisphere after acute stroke results in improved language performance ( 170 – 172 ).

4. Expert opinion

There are many challenges to aphasia diagnosis and treatment. One of the most fundamental challenges remains the significant gap in translating clinical research into practice. Only a small percentage of research findings will ultimately influence clinical practice, and the findings that do change clinical practice take many years to do so ( 173 , 174 ). There are many factors that contribute to this gap. However, the most obvious factor is that the majority of research treatment studies cannot be successfully implemented in clinical settings due to challenges such as time constraints, insurance coverage limitations, and lack of resources at clinical sites. Many research studies in aphasia find positive outcomes when they provide patients with many hours of language therapy or provide them with many hours of intensive language therapy per day ( 175 – 177 ), but most patients do not have access to this dosage or intensity of language therapy.

Both language therapy intensity and dosage are important considerations in aphasia treatment, yet the field has no clear definition of dosage versus intensity. The terms are sometimes used interchangeably to refer to the number of hours given in a specific period of time, or the total number of hours of therapy provided during a treatment study ( 178 ). Little research addresses the question of treatment intensity in acute/subacute recovery stages. Bakheit and colleagues ( 179 ) compared intensive treatment where therapy was delivered 5 hours per week for 12 weeks to standard non-intensive treatment of 2 hours per week for 12 weeks. No significant difference was found between groups, but the mean scores were consistently higher in the intensive group. Recent research suggests that patients do benefit from increased intensity even in the acute/subacute stages of stroke ( 180 – 182 ). Some researchers question how well patients will tolerate intensive therapy in the first few weeks following stroke, and have found patients are patients are more likely to drop out of high intensity treatments ( 179 , 183 ), however others have demonstrated that it is feasible to increase therapy intensity even in the early stages of stroke recovery ( 180 – 182 ).

Several studies in chronic aphasia have demonstrated that high intensity aphasia treatment is more beneficial than low intensity treatment ( 183 , 184 ). However, a recent review in chronic aphasia concluded that while some evidence suggests patients benefit more from intensive therapy, there is stronger evidence to suggest that patients benefit from lower intensity treatment in the chronic recovery phase ( 185 ). Pierce and colleagues ( 185 ) ultimately conclude that more evidence (i.e., randomized trials with large sample sizes) is required before it can be unequivocally stated that low vs. high intensity therapy is more likely to benefit patients with chronic aphasia. Future research must disentangle the effects of dosage and intensity, and moreover must consider real world constraints on clinical practice.

Additionally, advances in technology will allow clinicians to provide patients with therapy tools outside of the clinic room. Clinicians can provide patients with intensive homework programs provided through various tablet-based treatment apps. It is imperative for clinicians to educate and familiarize themselves with ways they can use new technology to provide their patients with the best possible treatment outcomes. Randomized trials are needed to evaluate the effect of computer or tablet delivered therapy, with or without clinician-delivered therapy, in both the clinic setting and via telerehabilitation. The COVID-19 pandemic has created an unprecedented situation that is limiting on-site clinical services. Therefore, it is critical that rehabilitation professionals and researchers find optimal ways to deliver therapy services to patients with aphasia. Offering telerehabilitation will also help expand the number of patients who can receive therapy as many patients have barriers preventing them from receiving in-person therapy.

Advances in technology will also impact diagnostic methods. Aphasia diagnosis has largely evolved beyond the traditional approach of classifying patients into specific syndromes and instead focuses on individualized patient profiles. Creating individualized patient profiles should rely on more than simply understanding the severity of comprehension and production deficits. Rather clinicians must investigate the underlying impairments that are contributing to deficits within each patient. For example, a patient may have a naming deficit that is rooted in phonological impairment and another patient may have an impaired semantic network. If clinicians take the time to discover the underlying impairment in each patient , then they will be able to provide targeted individualized therapy that will have a better likelihood of benefitting their patients.

Medications for the treatment of aphasia have had mixed success. Beneficial effects have been reported for several drugs including piracetam and donepezil when combined with language therapy. However, data on long-term benefits are limited. There is a paucity of large RCTs as the majority of the trials are small open-label trials or case studies. In addition, there is wide variation in participant characteristics (e.g., fluent vs. non-fluent aphasia), timing of intervention (acute vs. chronic), type of language therapy (e.g., auditory comprehension vs naming), therapy duration, medication dosage, and outcome measures, leading to inconsistent findings. Further, the neuroplastic changes that are taking place as a result of pharmacotherapy are still unclear. Effort should be directed to identify the optimal dosage and timing of administration of different drugs. In addition, large scale randomized controlled trials are needed to identify appropriate candidates using well-defined clinical criteria and neuroimaging techniques to understand the mechanism of neural recovery.

Non-invasive brain simulation techniques are increasing used to modulate brain plasticity and accelerate language recovery. However, it remains unclear which area of the brain (left, right, or cerebellum), and which kind of stimulation (inhibitory or excitatory) is more effective in augmenting aphasia treatment. To know which region to target with NIBS, we need a better understanding of the mechanisms underlying recovery from aphasia. Similar to pharmacotherapy, there are wide variations in experimental factors including different types of aphasia, lesion site and location, NIBS stimulation parameters, different types of language therapy, therapy duration, and different outcome measures. This presents a major challenge to interpreting the findings. Finally, there are several practical issues that need to be addressed before we can adopt tDCS in clinical settings including training of clinicians, affordability and reimbursement. It is also essential to include outcome measures that show that intervention (behavioral, brain stimulation or pharmacotherapy) makes a difference in functional communication or quality of life, rather than simply focusing on impairment-based outcome measures.

Research studies should focus on the individual factors and biomarkers that could predict NIBS and pharmacotherapy response. Blood and saliva biomarkers are good candidates given the ease of access of sample collection, the possibility of storing samples for further analyses, and the availability of commercial kits, making it easier to be replicated in clinical or research facilities. For example, Fridriksson and colleagues ( 186 ) show that the analysis of genetic polymorphisms of Brain-Derived Neurotrophic Factor (BDNF) may help to determine the response to tDCS combined with behavioral therapy in chronic stroke patients with aphasia Furthermore, novel machine learning approaches are being developed that will allow for more accurate prediction of individual outcomes and response to therapy using data from brain imaging, behavioral measures, or their combination ( 187 – 189 ). The goal is to reach a point where clinicians are able to easily synthesize behavioral, lesion, and genetic information using sophisticated machine learning algorithms to select individualized therapy techniques (e.g., best behavioral therapy plus the best neuromodulation approach) that will most benefit each patient.

Article highlights:

• Aphasia diagnostics should expand beyond simply classifying patients by aphasia syndrome. Instead an effort should be made to determine which linguistic and cognitive mechanisms are impaired.
• Comprehensive aphasia evaluation must include a thorough case history, assessments of linguistic/cognitive skills, and an appraisal of how functional communication has been affected by aphasia.
• Aphasia treatment must be individualized for patients in consideration of their goals, specific strengths, and deficits.
• Aphasia studies need to incorporate both impairment and functional based outcome measures. Aphasia treatment studies have largely focused on impairment-based outcomes (e.g., naming); however, an improvement of impairment level outcome naming is not always followed by an improvement of functional communication. Therefore, it is necessary that primary outcome measures incorporate changes in functional communication, behavior, and quality of life measures.
• Pharmacological agents already approved for the treatment of other neurological and psychiatric disorders have been studied in patients with post-stroke aphasia. Several small case studies, open-label trials, and small randomized clinical trials show that pharmacotherapy provides benefits in stroke patients with aphasia; however, benefits are not evident for all drugs and for all aphasia severity levels.
• Non-invasive brain stimulation (NIBS) technologies such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have shown promising results in case studies and clinical trials; however, these methods remain investigational for post-stroke aphasia and are not approved for clinical use.
• There is wide variation in protocols including stimulation location, stimulation intensity, number of treatment sessions, outcome measures, type of aphasia treatment, and time post-stroke. Determining optimal NIBS parameters as well as the mechanisms underlying treatment improvement is critical to facilitate transition to clinical practice.

Acknowledgments

The research reported in this paper was supported by the National Institutes of Health (National Institute on Deafness and Other Communication Disorders) through award R00 DC015554. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health.

Declaration of interests

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Papers of special note have been highlighted as either of interest (*) or of considerable interest (**) to readers.

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The Resolving Stroke and Aphasia A Case Study With Computerized Tomography

From the Departments of Audiology and Speech Pathology, and Radiology, Veterans Administration Hospital and Stanford University Medical Center, Palo Alto, Calif. Dr Naeser is now with the Veterans Administration Hospital, Boston.

• A 39-year-old man suffered an intracerebral hemorrhage in the region of the left internal capsule deep to Wernicke's area. The location of the lesion was confirmed by computerized tomography (CT) performed two days postictally. Two weeks after admission, the Boston Diagnostic Aphasia Examination (BDAE) disclosed Wernicke's aphasia. We hypothesize that the hematoma exerted pressure on Wernicke's cortical area, thus causing the resulting Wernicke's aphasia at that time. A CT scan three months later showed absorption of the hematoma, with a residual low-density lesion deep to Wernicke's area, in the region of the arcuate fasciculus. At that time, BDAE testing disclosed a mild conduction aphasia. Serial CT scanning combined with discriminating clinical evaluation of aphasia provides a valuable opportunity for study of the processes underlying stroke resolution and aphasia.

Naeser MA , Hayward RW. The Resolving Stroke and Aphasia A Case Study With Computerized Tomography. Arch Neurol. 1979;36(4):233–235. doi:10.1001/archneur.1979.00500400087016

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Case Study - Broca's Aphasia

Time Since Stroke: 6 months

Georgia had a stroke at a young age, losing her independent lifestyle as a teacher and gifted artist. She had to move back home with her parents and couldn't drive, but she had very good friends who maintained close contact with her. She had a great sense of humor. We let her redesign the office to encourage her pre-stroke designing skills.

Georgia had severe Broca's aphasia with apraxia. She mostly spoke in automatic phrases, such as "I don't know" or 1 word.

Assessment: Georgia maintained her knowledge of her Iphone and Ipad, which she used at times to speak for her (still 1 word). She rarely tried to speak, wanting to use her phone instead. Her goal was to return to work and become independent again.

Treatment: 6 weeks, then returned for another 4 week session

By the end of her program, Georgia spoke in 2-4 words at a time "help me, please" and "I want diet Coke". She started using speech more frequently than her phone, approximately 50-80% of the time. In social conversations, she responded more quickly and maintained a conversational rhythm. She could say 2-3 syllable words and wrote little notes for staff and her friends.

Her aphasia test score for speaking, understanding and repeating went from 32 to 45.7, a gain of 13.7 points . Her reading comprehension score went up 55% , and her caregiver rated improvements from 19%-46% in the areas of getting attention, recalling and saying names of people, and in participating in a group discussion about herself.

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Neural correlates of high frequency repetitive transcranial magnetic stimulation improvement in post-stroke non-fluent aphasia: a case study

Affiliation.

• 1 a Lafosse-Dammekens VOF , Hasselt , Belgium.
• PMID: 22963195
• DOI: 10.1080/13554794.2012.713493

Damage to the left inferior frontal gyrus (lIFG) affects language and can cause aphasia in stroke. Following left hemisphere damage it has been suggested that the homologue area in the right hemisphere compensates for lost functions. An increasing number of studies have demonstrated that inhibitory 1-Hz repetitive transcranial magnetic stimulation (rTMS) targeting the right IFG can be useful for enhancing recovery in aphasic patients. In the present study we applied activating high frequency (10-Hz) rTMS, which increases cortical excitability, to the damaged lIFG daily for 3 weeks. Pre- and post-TMS EEG are performed, as well as language function assessments with the Aachener Aphasia Test Battery. Results demonstrate a decrease in rIFG activity post rTMS and normalization for the lIFG for beta3 frequency band. Also increased activity was in the right supplementary motor area for beta3 frequency band. In comparison to pre-TMS the aphasic patient improved on repetition tests, for naming and comprehension. After rTMS increased functional connectivity was shown in comparison to before between the lIFG and the rIFG for theta and beta3 frequency band. This case report suggests that 10 Hz rTMS of the lIFG can normalize activity in the lIFG and right IFG possibly mediated via altered functional connectivity.

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