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Abstract Background Recent findings of a tight coupling between visual and auditory association cortices during multisensory perception in monkeys and humans raise the question whether consistent paired presentation of simple visual and auditory stimuli prompts conditioned responses in unimodal auditory regions or multimodal association cortex once visual stimuli are presented in isolation in a post-conditioning run. To address this issue fifteen healthy participants partook in a "silent" sparse temporal event-related fMRI study. In the first (visual control) habituation phase they were presented with briefly red flashing visual stimuli. In the second (auditory control) habituation phase they heard brief telephone ringing. In the third (conditioning) phase we coincidently presented the visual stimulus (CS) paired with the auditory stimulus (UCS). In the fourth phase participants either viewed flashes paired with the auditory stimulus (maintenance, CS-) or viewed the visual stimulus in isolation (extinction, CS+) according to a 5:10 partial reinforcement schedule. The participants had no other task than attending to the stimuli and indicating the end of each trial by pressing a button. Results During unpaired visual presentations (preceding and following the paired presentation) we observed significant brain responses beyond primary visual cortex in the bilateral posterior auditory association cortex (planum temporale, planum parietale) and in the right superior temporal sulcus whereas the primary auditory regions were not involved. By contrast, the activity in auditory core regions was markedly larger when participants were presented with auditory stimuli. Conclusion These results demonstrate involvement of multisensory and auditory association areas in perception of unimodal visual stimulation which may reflect the instantaneous forming of multisensory associations and cannot be attributed to sensation of an auditory event. More importantly, we are able to show that brain responses in multisensory cortices do not necessarily emerge from associative learning but even occur spontaneously to simple visual stimulation.

Background: It is unknown whether hypertensive microangiopathy or cerebral amyloid angiopathy (CAA) predisposes more to anticoagulant-associated intracerebral hemorrhage (AA-ICH). The purpose of our study was to determine whether AA-ICH is associated with lobar location and probable CAA., Methods: This was a cross-sectional analysis of patients with first-ever spontaneous ICH admitted to a tertiary hospital in Boston, between 2008 and 2023. Univariable and multivariable logistic regression were used to investigate the association between anticoagulation use and both lobar hemorrhage location and probable CAA on magnetic resonance imaging (MRI) by Boston Criteria 2.0 or computed tomography by Simplified Edinburgh Criteria., Results: A total of 1104 patients (mean [SD] age, 73 [12]; 499 females [45.0%]) were included. Of the 1104 patients, 268 (24.3%) had AA-ICH: 148 (55.2%) with vitamin K antagonists and 107 (39.9%) with direct oral anticoagulants. Brain MRI was performed in 695 (63.0%) patients. The proportion of patients with lobar hemorrhage was not different between those with and without AA-ICH (121/268 [45.1%] versus 424/836 [50.7%]; odds ratio [OR], 0.80 [95% CI, 0.61-1.05]; P =0.113). Patients with AA-ICH were less likely to have probable CAA on MRI (17/146 [11.6%] versus 127/549 [23.1%]; OR, 0.44 [95% CI, 0.25-0.75]; P =0.002) and probable CAA on MRI or computed tomography if MRI not performed (27/268 [10.0%] versus 200/836 [23.9%]; OR, 0.36 [95% CI, 0.23-0.55]; P <0.001). Among patients with AA-ICH, there were no differences in the proportion with lobar hemorrhage (63/148 [42.6%] versus 46/107 [43.0%]; OR, 1.02 [95% CI, 0.62-1.68]; P =0.946) or probable CAA on MRI (10/72 [13.9%] versus 7/69 [10.1%]; OR, 0.70 [95% CI, 0.25-1.96]; P =0.495) between vitamin K antagonists and direct oral anticoagulant users., Conclusions: AA-ICH was not associated with lobar hemorrhage location but was associated with reduced odds of probable CAA. These results suggest that hypertensive microangiopathy may predispose more toward incident AA-ICH than CAA and emphasize the importance of blood pressure control among anticoagulant users. These findings require replication in additional cohorts., Competing Interests: Dr Selim receives grant funding from the National Institute of Neurological Disorders and Stroke and National Institute of Aging, unrelated to the current study. He receives compensation from MedRhythms Inc and Valin Technologies for consultant services, compensation from Alnylam Pharmaceuticals for data and safety monitoring services, and has stock holdings in NeuGel. He has authored a section on secondary prevention of intracerebral hemorrhage and is employed by Beth Israel Deaconess Medical Center. The other authors report no conflicts.

Introduction: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life., Methods: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE., Conclusion: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins., (S. Karger AG, Basel.)

Background: Cerebellar intracerebral hemorrhage (cICH) is often attributed to hypertension or cerebral amyloid angiopathy (CAA). However, deciphering the exact etiology can be challenging. A recent study reported a topographical etiologic relationship with superficial cICH secondary to CAA. We aimed to reexamine this relationship between topography and etiology in a separate cohort of patients and using the most recent Boston criteria version 2.0., Methods: We performed a retrospective analysis of consecutive patients with primary cICH admitted to a tertiary academic center between 2000 and 2022. cICH location on brain computed tomography/magnetic resonance imaging scan(s) was divided into strictly superficial (cortex, surrounding white matter, vermis) versus deep (cerebellar nuclei, deep white matter, peduncular region) or mixed (both regions). Magnetic resonance imaging was rated for markers of cerebral small vessel disease. We assigned possible/probable versus absent CAA using Boston criteria 2.0., Results: We included 197 patients; 106 (53.8%) were females, median age was 74 (63-82) years. Fifty-six (28%) patients had superficial cICH and 141 (72%) deep/mixed cICH. Magnetic resonance imaging was available for 112 (57%) patients (30 [26.8%] with superficial and 82 [73.2%] with deep/mixed cICH). Patients with superficial cICH were more likely to have possible/probable CAA (48.3% versus 8.6%; odds ratio [OR], 11.43 [95% CI, 3.26-40.05]; P <0.001), strictly lobar cerebral microbleeds (51.7% versus 6.2%; OR, 14.18 [95% CI, 3.98-50.50]; P <0.001), and cortical superficial siderosis (13.8% versus 1.2%; OR, 7.70 [95% CI, 0.73-80.49]; P =0.08). Patients with deep/mixed cICH were more likely to have deep/mixed cerebral microbleeds (59.2% versus 3.4%; OR, 41.39 [95% CI, 5.01-341.68]; P =0.001), lacunes (54.9% versus 17.2%; OR, 6.14 [95% CI, 1.89-19.91]; P =0.002), severe basal ganglia enlarged perivascular spaces (36.6% versus 7.1%; OR, 7.63 [95% CI, 1.58-36.73]; P =0.01), hypertension (84.4% versus 62.5%; OR, 3.43 [95% CI, 1.61 to -7.30]; P =0.001), and higher admission systolic blood pressure (172 [146-200] versus 146 [124-158] mm Hg, P <0.001)., Conclusions: Our results suggest that superficial cICH is strongly associated with CAA whereas deep/mixed cICH is strongly associated with hypertensive arteriopathy., Competing Interests: Disclosures Dr Selim serves on the advisory boards of MedRhythms, Inc, for consultant services. The other authors report no conflicts.

Objectives: A post-hoc analysis of the ICH Deferoxamine (i-DEF) trial was performed to examine any associations pre-ICH statin use may have with ICH volume, PHE volume, and clinical outcomes., Materials and Methods: Baseline characteristics were assessed. Various ICH and PHE parameters were measured via a quantitative, semi-automated method at baseline and follow-up CT scans 72-96 h later. A multivariable logistic regression model was created, adjusting for the variables that were significantly different on univariable analyses (p < 0.05), to assess any associations between pre-ICH statin use and measures of ICH and PHE, as well as good clinical outcome (mRS ≤2), at 90 and 180 days., Results: 262 of 291 i-DEF participants had complete data available for analysis. 69 (26.3 %) used statins prior to ICH onset. Pre-ICH statin users had higher prevalences of hypertension, diabetes, and prior ischemic stroke; higher concomitant use of antihypertensives and antiplatelets; and higher blood glucose level at baseline. On univariable analyses, pre-ICH statin users had smaller baseline ICH volume and PHE volume on repeat scan, as well as smaller changes in relative PHE (rPHE) volume and edema extension distance (EED) between the baseline and repeat scans. In the multivariable analysis, none of the ICH and PHE measures or good clinical outcome was significantly associated with pre-ICH statin use., Conclusion: Pre-ICH statin use was not associated with measures of ICH or PHE, their growth, or clinical outcomes. These findings do not lend support to either overall protective or deleterious effects from statin use before or after ICH., Competing Interests: Declaration of Competing Interest Dr. Magdy Selim receives grant funding from the NINDS (related to and outside of the current work), royalties from Up to Date and Cambridge University Press. He serves on the Advisory Board of MedRhythms Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: The relationship between perihematomal edema (PHE) and intracerebral hemorrhage (ICH) outcomes is uncertain. Given newly published studies, we updated a previous systematic review and meta-analysis assessing the prognostic impact of PHE on ICH outcomes., Materials and Methods: Databases were searched through September 2022 using pre-defined keywords. Included studies used regression to examine the association between PHE and functional outcome (assessed by modified Rankin Scale [mRS]) and mortality. The study quality was assessed using the Newcastle-Ottawa Scale. The overall pooled effect, and secondary analyses exploring different subgroups were obtained by entering the log transformed odds ratios and their confidence intervals into a DerSimonian-Laird random effects meta-analysis., Results: Twenty-eight studies (n=8655) were included. The pooled effect size for overall outcome (mRS and mortality) was 1.05 (95% CI 1.03, 1.07; p<0.00). In secondary analyses, PHE volume and growth effect sizes were 1.03 (CI 1.01, 1.05) and 1.12 (CI 1.06, 1.19), respectively. Results of subgroup analyses assessing absolute PHE volume and growth at different time points were: baseline volume 1.02 (CI 0.98, 1.06), 72-hour volume 1.07 (CI 0.99, 1.16), growth at 24 hours 1.30 (CI 0.96, 1.74) and growth at 72 hours 1.10 (CI 1.04, 1.17). Heterogeneity across studies was substantial., Conclusions: This meta-analysis indicates that PHE growth, especially within the first 24 hours after ictus, has a stronger impact on functional outcome and mortality than PHE volume. Definitive conclusions are limited by the large variability of PHE measures, heterogeneity, and different evaluation time points between studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Gender disparities among principal investigators of clinical trials (CT) can have implications regarding the areas of investigation, methods, conduct, trial enrollment, and interpretation of results. An estimation of the gender gap in the leadership of stroke-related CTs from North America has to date not been undertaken., Methods: We extracted information about stroke-related CTs between 2011 and 2020 from www., Clinicaltrials: gov and PubMed. We examined the gender distribution according to the academic credentials and the trial type. The gender of PIs and authors was determined using gender package in R, which identifies gender using historical data from the United States. Additionally, we obtained information from Association of American Medical Colleges and the Accreditation Council for Graduate Medical Education data resource books on the gender composition of full-time neurology faculty, neurology residents and vascular neurology fellows., Results: In these analyses of 821 CTs registered on Clinicaltrials.gov and 110 trials published on PubMed, we found that gender disparity among the PIs, first and last authors have persisted over the last decade without any significant trend toward parity ( P >0.05). On examining the gender distribution according to academic credentials and trial type, we found that men were over-represented in the sub-group of PIs with an MD degree (78.11% versus 21.87%; P <0.01) and those leading acute stroke trials (86.04% versus 13.89%; P <0.01). We also found that a lower proportion of women neurology residents pursued a vascular neurology fellowship during this period (33.5% versus 42.5%; P <0.05)., Conclusions: Our results show that the favorable trend toward gender parity seen in Neurology faculty over the last decade has not translated to the same in the leadership of CTs. Our findings merit further investigation and a re-examination of efforts toward inclusion of women as leaders of stroke-related CTs.

Patients with large left-hemisphere lesions and post-stroke aphasia often remain nonfluent. Melodic intonation therapy (MIT) may be an effective alternative to traditional speech therapy for facilitating recovery of fluency in those patients. In an open-label, proof-of-concept study, 14 subjects with nonfluent aphasia with large left-hemisphere lesions (171 ± 76 cc) underwent two speech/language assessments before, one at the midpoint, and two after the end of 75 sessions (1.5 h/session) of MIT. Functional MR imaging was done before and after therapy asking subjects to vocalize the same set of 10 bi-syllabic words. We found significant improvements in speech output after a period of intensive MIT (75 sessions for a total of 112.5 h) compared to two pre-therapy assessments. Therapy-induced gains were maintained 4 weeks post-treatment. Imaging changes were seen in a right-hemisphere network that included the posterior superior temporal and inferior frontal gyri, inferior pre- and postcentral gyri, pre-supplementary motor area, and supramarginal gyrus. Functional changes in the posterior right inferior frontal gyri significantly correlated with changes in a measure of fluency. Intense training of intonation-supported auditory-motor coupling and engaging feedforward/feedback control regions in the unaffected hemisphere improves speech-motor functions in subjects with nonfluent aphasia and large left-hemisphere lesions., (© 2022 New York Academy of Sciences.)

Background: Conflicting data exist regarding the association of perihematomal edema (PHE) with outcomes after intracerebral hemorrhage (ICH). We performed a post hoc analysis of the ICH Deferoxamine trial to examine whether an early change in ventricular size (VS), as a composite measure of PHE growth and mass effect, intraventricular hemorrhage, and hydrocephalus, is a more accurate predictor of outcome than PHE measures alone., Methods: Computerized tomography scans were performed at baseline and after 72-96 h. We evaluated measures of PHE and change in VS as predictors of outcome, assessed by a dichotomized modified Rankin Scale score (0-2 versus 3-6), primarily at 90 days and secondarily at 30 days. A multivariable logistic regression model was fitted for each predictor, with adjustment for the same confounders., Results: A total of 248 participants were included after we excluded those requiring external ventricular drains. On univariate analyses, older age, female sex, lower Glasgow Coma Scale score and baseline temperature, greater ICH volume, absolute PHE volume, edema extension distance at presentation, lesser changes in relative PHE volume and edema extension distance, and an increase in VS were associated with poor outcome. In multivariable analyses, only the increase in VS was associated with lower odds of modified Rankin Scale scores 0-2 at 90 days (odds ratio 0.927, 95% confidence interval 0.866-0.970, p = 0.001) and 30 days (odds ratio 0.931, 95% confidence interval 0.888-0.975, p = 0.003)., Conclusions: Within the context of a randomized controlled trial with standardized imaging and functional assessments, we did not find significant associations between measures of PHE and outcome but documented an independent association between early increase in VS and lower odds of good clinical outcome., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Dysphagia is a common consequence of intracerebral hemorrhages (ICH). It can lead to enduring impairments of dietary intake and the requirement for feeding via percutaneous gastrostomy (PEG) tubes. However, variabilities in the course of swallowing recovery after ICH make it difficult to anticipate the need for PEG placement in an individual patient. A new tool called the GRAVo score was recently developed to predict PEG tube placement after an ICH but has not been externally validated. Our study aims were to externally validate the GRAVo score in a multicenter cohort and reexamine the role of race in predicting PEG placement, given the uncertain biological plausibility for this relationship observed in the derivation cohort., Methods: Patients for this analysis were selected from a previously completed multicenter, randomized, double-blind futility design clinical trial, the Intracerebral Hemorrhage Deferoxamine trial, and underwent a retrospective review of prospectively collected data. The GRAVo scores were computed by using previously established methods using the following variables: Glasgow Coma Scale ≤ 12 (2 points), race (1 point for Black), age > 50 years (2 points), and ICH volume > 30 mL (1 point). Association of GRAVo scores with PEG placement were examined by using logistic regression analysis after adjustment for exposure to deferoxamine. Model performance was estimated by using area under the receiving operating characteristic curve (AUROC). Subsequently, a second model was created by excluding scores for race, and the AUROC of both models were compared., Results: A total of 291 patients with complete data points served as the study cohort; 38 (13%) underwent PEG placement. The median GRAVo score for patients in the PEG and non-PEG groups were 4 (interquartile range 3-4) versus 2 (interquartile range 2-3), respectively (p < 0.0001). External validation of the GRAVo score yielded an AUROC of 0.7008 (95% confidence interval 0.6036-0.78); the model obtained without assignment of scores for the variable race yielded an AUROC of 0.6958 (95% confidence interval 0.6124-0.7891). The receiver operating characteristic curves from both models demonstrated close overlap., Conclusions: The results of our external validation demonstrate the validity of GRAVo scores for predicting PEG tube placement after an ICH. However, its performance was more modest compared with that of the derivation cohort. Inclusion of the race variable had no measurable effect on model performance. Differences in patient characteristics between these cohorts may have influenced our results. These findings should be taken into consideration when using the GRAVo score to assist clinical decision making on PEG placement after an ICH., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Perihematomal edema (PHE) has been proposed as a radiological marker of secondary injury and therapeutic target in intracerebral hemorrhage (ICH). We conducted a systematic review and meta-analysis to assess the prognostic impact of PHE on functional outcome and mortality in patients with ICH., Methods: We searched major databases through December 2020 using predefined keywords. Any study using logistic regression to examine the association between PHE or its growth and functional outcome was included. We examined the overall pooled effect and conducted secondary analyses to explore the impact of individual PHE measures on various outcomes separately. Study quality was assessed by three independent raters using the Newcastle-Ottawa Scale. Odds ratios (per 1-unit increase in PHE) and their confidence intervals (CIs) were log transformed and entered into a DerSimonian-Laird random-effects meta-analysis to obtain pooled estimates of the effect., Results: Twenty studies (n = 6633 patients) were included in the analysis. The pooled effect size for overall outcome was 1.05 (95% CI 1.02-1.08; p < 0.00). For the following secondary analyses, the effect size was weak: mortality (1.01; 95% CI 0.90-1.14), functional outcome (1.04; 95% CI 1.02-1.07), both 90-day (1.06; 95% CI 1.02-1.11), and in-hospital assessments (1.04; 95% CI 1.00-1.08). The effect sizes for PHE volume and PHE growth were 1.04 (95% CI 1.01-1.07) and 1.14 (95% CI 1.04-1.25), respectively. Heterogeneity across studies was substantial except for PHE growth., Conclusions: This meta-analysis demonstrates that PHE volume within the first 72 h after ictus has a weak effect on functional outcome and mortality after ICH, whereas PHE growth might have a slightly larger impact during this time frame. Definitive conclusions are limited by the large variability of PHE measures, heterogeneity, and different evaluation time points between studies., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Dysphagia is a serious stroke complication but lacks effective therapy. We investigated safety and preliminary efficacy of anodal transcranial direct current stimulation (atDCS) paired with swallowing exercises in improving post-stroke dysphagia from an acute unilateral hemispheric infarction (UHI). We conducted a double-blind, early phase-2 randomized controlled trial, in subjects (n = 42) with moderate-severe dysphagia [Penetration and Aspiration Scale (PAS) score ≥ 4], from an acute-subacute UHI. Subjects were randomized to Low-Dose, High-Dose atDCS or Sham stimulation for 5 consecutive days. Primary safety outcomes were incidence of seizures, neurological, motor, or swallowing function deterioration. Primary efficacy outcome was a change in PAS scores at day-5 of intervention. Main secondary outcome was dietary improvement at 1-month, assessed by Functional Oral Intake (FOIS) score. No differences in pre-defined safety outcomes or adjusted mean changes in PAS, FOIS scores, between groups, were observed. Post-hoc analysis demonstrated that 22 /24 subjects in the combined atDCS group had a clinically meaningful dietary improvement (FOIS score ≥ 5) compared to 8 /14 in Sham (p = 0.037, Fisher-exact). atDCS application in the acute-subacute stroke phase is safe but did not decrease risk of aspiration in this early phase trial. The observed dietary improvement is promising and merits further investigation., (© 2022. The Author(s).)

Objective: To investigate the frequency, time-course and predictors of intracerebral haemorrhage (ICH), recurrent convexity subarachnoid haemorrhage (cSAH), and ischemic stroke after cSAH associated with cerebral amyloid angiopathy (CAA)., Methods: We performed a systematic review and international individual patient-data pooled analysis in patients with cSAH associated with probable or possible CAA diagnosed on baseline MRI using the modified Boston criteria. We used Cox proportional hazards models with a frailty term to account for between-cohort differences., Results: We included 190 patients (mean age 74.5 years; 45.3% female) from 13 centers with 385 patient-years of follow-up (median 1.4 years). The risks of each outcome (per patient-year) were: ICH 13.2% (95% CI 9.9-17.4); recurrent cSAH 11.1% (95% CI 7.9-15.2); combined ICH, cSAH, or both 21.4% (95% CI 16.7-26.9), ischemic stroke 5.1% (95% CI 3.1-8) and death 8.3% (95% CI 5.6-11.8). In multivariable models, there is evidence that patients with probable CAA (compared to possible CAA) had a higher risk of ICH (HR 8.45, 95% CI 1.13-75.5, p = 0.02) and cSAH (HR 3.66, 95% CI 0.84-15.9, p = 0.08) but not ischemic stroke (HR 0.56, 95% CI 0.17-1.82, p = 0.33) or mortality (HR 0.54, 95% CI 0.16-1.78, p = 0.31)., Conclusions: Patients with cSAH associated with probable or possible CAA have high risk of future ICH and recurrent cSAH. Convexity SAH associated with probable (vs possible) CAA is associated with increased risk of ICH, and cSAH but not ischemic stroke. Our data provide precise risk estimates for key vascular events after cSAH associated with CAA which can inform management decisions., (© 2021. The Author(s).)

Background: Transcranial direct current stimulation (tDCS) has been investigated as a tool for dysphagia recovery after stroke in several single-center randomized controlled trials (RCT)., Objective: The aim of this investigation was to quantitatively evaluate the effect of tDCS on dysphagia recovery after a stroke utilizing a systematic review and meta-analysis., Methods: Major databases were searched through October 2019 using a pre-defined set of criteria. Any RCT investigating the efficacy of tDCS in post-stroke dysphagia using a standardized dysphagia scale as outcome measure was included. Studies were assessed for risk of bias and quality using the Physiotherapy Evidence Database (PEDro) scale. Effect sizes were calculated from extracted data and entered into a random effects analysis to obtain pooled estimates of the effect., Results: Seven RCTs with a total sample size of 217 patients fulfilled the criteria and were included in the analysis. The overall results revealed a small but statistically significant pooled effect size (0.31; CI 0.03, 0.59; p = 0.03). The subgroup which explored the stimulation intensity yielded a moderately significant effect size for the low-intensity stimulation group (g = 0.44; CI = 0.08, 0.81 vs. g = 0.15, CI - 0.30, 0.61). For the other subgroup analyses, neither comparisons of affected vs. unaffected hemisphere or acute vs. chronic stroke phase revealed a significant result., Conclusion: This meta-analysis demonstrates a modest but significant beneficial effect of tDCS on improving post-stroke dysphagia. Whether benefits from this intervention are more pronounced in certain patient subgroups and with specific stimulation protocols requires further investigation.

Background: With ever-increasing numbers of patients undergoing elective total knee arthroplasty (TKA) and as TKA is performed in increasingly younger patients, patient demands and expectations have also increased. With improved patient outcomes, new PROMs with heightened discriminatory power in well-performing patients are needed. The present study aimed to translate and validate the Italian version of the Forgotten Joint Score (FJS-12) as a tool for evaluating pre-operative through longitudinal post-operative outcomes in an Italian population., Methods: In this prospective study, patients with unilateral osteoarthritis, undergoing TKA surgery between May 2015 and December 2017 were recruited to participate in the study. The FJS-12 and WOMAC were collected pre-operatively and at six and 12 months post-operatively. According to the COSMIN checklist, reliability, internal consistency, validity, responsiveness, effect size, and ceiling effects and floor effects were evaluated., Results: One hundred twenty patients completed the study, 66 of which participated in the evaluation of test-retest reliability. Good test-retest reliability was found (ICC = 0.90). The FJS-12 also showed excellent internal consistency (Cronbach α = 0.81). Construct validity with the WOMAC, as a measure of the Pearson correlation coefficient, was moderate (r = 0.45 pre-operatively; r = 0.46 at 6 months and r = 0.42 at 12 months post-operatively). From six to 12 months, the change was slightly greater for the WOMAC than for the FJS-12 patients (effect size d = 0.94; d = 0.75, respectively). At 12-months follow-up, the ceiling effects reflecting the maximum score were 12% for the FJS-12 and 6% for the WOMAC; however, scores within 10% of the maximum score were comprised 30% of the FJS-12 scores and 59% for the WOMAC., Conclusion: The Italian FJS-12 demonstrated strong measurement properties in terms of reliability, internal consistency, and construct validity in TKA patients. Furthermore, a more detailed look at ceiling effects shows a superior discriminatory capacity when compared to the WOMAC at 12-months follow-up, particularly in better-performing patients., Trial Registration: clinicaltrials.gov NCT03805490. Registered 18 January 2019 (retrospectively registered).

Goal: We performed a systematic review and meta-analysis aiming to clarify the relationship between acid-suppressive medication (ASM) and the risk of pneumonia in acute stroke., Methods: The included studies examined patients with an acute ischemic and/or hemorrhagic stroke, assessed the relationship of one or both groups of ASM, histamine-2 receptor antagonist (H2RA) and proton-pump inhibitor (PPI), as a variable of interest, and used the occurrence of hospital-acquired pneumonia (HAP) as an outcome measure. The search was conducted in MEDLINE, Cochrane, Embase, and Google Scholar. Random-effects meta-analyses were used to obtain pooled estimates of the effect., Results: 5 retrospective cohort-studies fulfilled study criteria. The results revealed a higher risk of pneumonia for both, patients receiving PPI (adjusted relative risk [RR] 2.37, 95% confidence interval [CI] 1.36-4.17, I 2 0%) and H2RAs (adjusted RR 1.73, 95% CI 0.74-4.25, I 2 68.3%), although the latter did not reach statistical significance. A comparison of the overall acid versus non-acid groups using unadjusted values yielded likewise an increased risk for pneumonia for patients receiving ASM (unadjusted RR 4.65, 95% CI 1.64-13.16, I 2 93.3%)., Conclusion: Results of this meta-analysis show an increased risk for HAP in acute stroke patients who receive ASM, particularly those exposed to PPIs. Larger, well-controlled studies in acute stroke populations are needed to establish a clearer association between ASM and HAP. These results, however, urge caution when prescribing ASM - especially to stroke patients considered to be at high risk for pneumonia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Functional imaging studies have provided insight into the effect of rate on production of syllables, pseudowords, and naturalistic speech, but the influence of rate on repetition of commonly-used words/phrases suitable for therapeutic use merits closer examination. Aim: To identify speech-motor regions responsive to rate and test the hypothesis that those regions would provide greater support as rates increase, we used an overt speech repetition task and functional magnetic resonance imaging (fMRI) to capture rate-modulated activation within speech-motor regions and determine whether modulations occur linearly and/or show hemispheric preference. Methods: Twelve healthy, right-handed adults participated in an fMRI task requiring overt repetition of commonly-used words/phrases at rates of 1, 2, and 3 syllables/second (syll./sec.). Results: Across all rates, bilateral activation was found both in ventral portions of primary sensorimotor cortex and middle and superior temporal regions. A repeated measures analysis of variance with pairwise comparisons revealed an overall difference between rates in temporal lobe regions of interest (ROIs) bilaterally ( p < 0.001); all six comparisons reached significance ( p < 0.05). Five of the six were highly significant ( p < 0.008), while the left-hemisphere 2- vs. 3-syll./sec. comparison, though still significant, was less robust ( p = 0.037). Temporal ROI mean beta-values increased linearly across the three rates bilaterally. Significant rate effects observed in the temporal lobes were slightly more pronounced in the right-hemisphere. No significant overall rate differences were seen in sensorimotor ROIs, nor was there a clear hemispheric effect. Conclusion: Linear effects in superior temporal ROIs suggest that sensory feedback corresponds directly to task demands. The lesser degree of significance in left-hemisphere activation at the faster, closer-to-normal rate may represent an increase in neural efficiency (and therefore, decreased demand) when the task so closely approximates a highly-practiced function. The presence of significant bilateral activation during overt repetition of words/phrases at all three rates suggests that repetition-based speech production may draw support from either or both hemispheres. This bihemispheric redundancy in regions associated with speech-motor control and their sensitivity to changes in rate may play an important role in interventions for nonfluent aphasia and other fluency disorders, particularly when right-hemisphere structures are the sole remaining pathway for production of meaningful speech.

Background: Many patients with acute intracerebral hemorrhages (ICHs) undergo endotracheal intubation with subsequent mechanical ventilation (MV) for "airway protection" with the intent to prevent aspiration, pneumonias, and its related mortality. Conversely, these procedures may independently promote pneumonia, laryngeal trauma, dysphagia, and adversely affect patient outcomes. The net benefit of intubation and MV in this patient cohort has not been systematically investigated., Methods: We conducted a large single-center observational cohort study to examine the independent association between endotracheal intubation and MV, hospital-acquired pneumonia (HAP), and in-hospital mortality (HM) in patients with ICH. All consecutive patients admitted with a primary diagnosis of a spontaneous ICH to a tertiary care hospital in Boston, Massachusetts, from June 2000 through January 2014, who were ≥18 years of age and hospitalized for ≥2 days were eligible for inclusion. Patients with pneumonia on admission, or those having brain or lung neoplasms were excluded. Our exposure of interest was endotracheal intubation and MV during hospitalization; our primary outcomes were incidence of HAP and HM, ascertained using International Classification of Diseases-9 and administrative discharge disposition codes, respectively, in patients who underwent endotracheal intubation and MV versus those who did not. Multivariable logistic regression was used to control for confounders., Results: Of the 2,386 hospital admissions screened, 1,384 patients fulfilled study criteria and were included in the final analysis. A total of 507 (36.6%) patients were intubated. Overall 133 (26.23%) patients in the intubated group developed HAP versus 41 (4.67%) patients in the non-intubated group (p < 0.0001); 195 (38.5%) intubated patients died during hospitalization compared to 48 (5.5%) non-intubated patients (p < 0.0001). After confounder adjustments, OR for HAP and HM, were 4.23 (95% CI 2.48-7.22; p < 0.0001) and 4.32 (95% CI 2.5-7.49; p < 0.0001) with c-statistics of 0.79 and 0.89, in the intubated versus non-intubated patients, respectively., Conclusion: In this large hospital-based cohort of patients presenting with an acute spontaneous ICH, endotracheal intubation and MV were associated with increased odds of HAP and HM. These findings urge further examination of the practice of intubation in prospective studies., (© 2018 S. Karger AG, Basel.)

Background: Computational analysis of swallowing mechanics (CASM) is a method that utilizes multivariate shape change analysis to uncover covariant elements of pharyngeal swallowing mechanics associated with impairment using videofluoroscopic swallowing studies. The goals of this preliminary study were to (1) characterize swallowing mechanics underlying stroke-related dysphagia, (2) decipher the impact of left and right hemispheric strokes on pharyngeal swallowing mechanics, and (3) determine pharyngeal swallowing mechanics associated with penetration-aspiration status., Methods: Videofluoroscopic swallowing studies of 18 dysphagic patients with hemispheric infarcts and age- and gender-matched controls were selected from well-controlled data sets. Patient data including laterality and penetration-aspiration status were collected. Coordinates mapping muscle group action during swallowing were collected from videos. Multivariate morphometric analyses of coordinates associated with stroke, affected hemisphere, and penetration-aspiration status were performed., Results: Pharyngeal swallowing mechanics differed significantly in the following comparisons: stroke versus controls (D = 2.19, P < .0001), right hemispheric stroke versus controls (D = 3.64, P < .0001), left hemispheric stroke versus controls (D = 2.06, P < .0001), right hemispheric stroke versus left hemispheric stroke (D = 2.89, P < .0001), and penetration-aspiration versus within normal limits (D = 2.25, P < .0001). Differences in pharyngeal swallowing mechanics associated with each comparison were visualized using eigenvectors., Conclusions: Whereas current literature focuses on timing changes in stroke-related dysphagia, these data suggest that mechanical changes are also functionally important. Pharyngeal swallowing mechanics differed by the affected hemisphere and the penetration-aspiration status. CASM can be used to identify patient-specific swallowing impairment associated with stroke injury that could help guide rehabilitation strategies to improve swallowing outcomes., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Pneumonia is a serious but a preventable stroke complication. Prediction scales for post-stroke pneumonia have been proposed with an intent to improve surveillance and prevention but they remain under-utilized in clinical practice. Most existing scales were developed using both ventilated and non-ventilated patients which may affect their accuracy. We derived and validated a novel, pragmatic scale to predict hospital-acquired pneumonia (HAP) after stroke employing only a non-ventilated stroke cohort., Methods: All consecutive patients admitted with acute stroke to a large hospital in Boston, Massachusetts, were identified using International Classification of Diseases, 9th revision (ICD-9) codes for acute ischemic strokes, intracerebral hemorrhages and confirmed by chart review. The following exclusion criteria were used: stroke occurring after hospitalization, pneumonia on admission, intubation, presence of brain or lung neoplasms, admission<48hours duration. HAP was defined using discharge ICD-9 codes. The association of relevant covariates with HAP was analyzed using multivariable stepwise logistic regression analysis to develop a scoring system and validated using bootstrapping., Results: A total of 1644 patients met study criteria; 144 (8.8%) developed HAP. An 8-point pneumonia prediction scale (ACDD 4 ) was derived using significant covariates (age≥75=1; congestive heart failure=1; dysarthria=1; dysphagia=4). The risk of pneumonia varied between 2% and 33.9% with scores of 0 to 7, respectively. The c-statistic of the final model was 0.82 and bootstrap validation c-statistic was 0.81., Conclusion: ACDD 4 scale is a promising tool for predicting HAP in non-ventilated stroke patients that can be easily computed at the patient's bedside. Subject term: cerebrovascular disease/stroke., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Importance: Transient symptoms from an intracerebral hemorrhage (ICH) are not well recognized and have previously not been reported., Objective: To describe the clinical presentations and neuroimaging findings in a subset of patients with ICH presenting with transient neurological signs and symptoms., Design, Setting, and Participants: Clinical case series in which the hospital database of a large academic center in Boston, Massachusetts, was searched using International Classification of Diseases, Ninth Revision code 431 from June 1, 2000, to August 31, 2014, to identify patients with ICH who had transient deficits that resolved completely within 24 hours of symptom onset., Main Outcomes and Measures: Clinical presentation, neuroimaging findings, and prognosis., Results: Among 3207 consecutive patients with ICH initially screened, 17 fulfilled study criteria (median age, 65 years [interquartile range, 56-73 years]; 11 male). In most patients, recovery from neurological symptoms started within a few hours after onset. Most hemorrhages in this cohort were small, with a mean (SD) hematoma volume of 17 (9.9) mL, and were subcortical in location. One patient died of hemorrhage recurrence., Conclusions and Relevance: Patients with ICH can present with rapidly resolving deficits resembling transient ischemic attacks. Recognition of these instances is important to avoid delays in investigations and to manage these cases appropriately.

Background: Pneumonia is a major complication of stroke, but effective prevention strategies are lacking. Since aspiration of oropharyngeal secretions is the primary mechanism for development of stroke-associated pneumonia, strategies that decrease oral colonization with pathogenic bacteria may help curtail pneumonia risk. We therefore hypothesized that systematic oral care protocols can help decrease pneumonia risk in hospitalized stroke patients. In this study, we investigated the impact of a systematic oral hygiene care (OHC) program in reducing hospital-acquired pneumonia in patients with acute-subacute stroke., Methods: This study compared the proportion of pneumonia cases in hospitalized stroke patients before and after implementation of a systematic OHC intervention. All patients hospitalized with acute ischemic stroke or intracerebral hemorrhage admitted to a large, urban academic medical center in Boston, Mass., USA from May 31, 2008, to June 1, 2010 (epoch prior to implementation of OHC), and from January 1, 2012, to December 31, 2013 (epoch after full implementation of OHC), who were 18 years of age and hospitalized for ≥ 2 days were eligible for inclusion. The cohort in the first epoch constituted the control group whereas the cohort in the second epoch formed the intervention group. Multivariate logistic regression was used to control for confounders. The main outcome measure was hospital-acquired pneumonia, defined via International Classification of Diseases, Ninth Revision, Clinical Modification codes., Results: The cohort comprised 1,656 admissions (707 formed historical controls; 949 were in the intervention group). The unadjusted incidence of hospital-acquired pneumonia was lower in the group assigned to OHC compared to controls (14 vs. 10.33%; p = 0.022) with an unadjusted OR of 0.68 (95% CI 0.48-0.95; p = 0.022). After adjustment for influential confounders, the OR of hospital-acquired pneumonia in the intervention group remained significantly lower at 0.71 (95% CI 0.51-0.98; p = 0.041)., Conclusion: In this large hospital-based cohort of patients admitted with acute stroke, systematic OHC use was associated with decreased odds of hospital-acquired pneumonia., (© 2015 S. Karger AG, Basel.)

Goal: Dysphagia is a major stroke complication but lacks effective therapy that can promote recovery. Noninvasive brain stimulation with and without peripheral sensorimotor activities may be an attractive treatment option for swallowing recovery but has not been systematically investigated in the stroke population. This article describes the study design of the first prospective, single-center, double-blinded trial of anodal versus sham transcranial direct current stimulation (tDCS) used in combination with swallowing exercises in patients with dysphagia from an acute ischemic stroke. The aim of this study is to gather safety data on cumulative sessions of tDCS in acute-subacute phases of stroke, obtain information about effects of this intervention on important physiologic and clinically relevant swallowing parameters, and examine possible dose effects., Methods: Ninety-nine consecutive patients with dysphagia from an acute unilateral hemispheric infarction with a Penetration and Aspiration Scale (PAS) score of 4 or more and without other confounding reasons for dysphagia will be enrolled at a single tertiary care center. Subjects will be randomized to either a high or low dose tDCS or a sham group and will undergo 10 sessions over 5 consecutive days concomitantly with effortful swallowing maneuvers. The main efficacy measures are a change in the PAS score before and after treatment; the main safety measures are mortality, seizures, neurologic, motor, and swallowing deterioration., Conclusions: The knowledge gained from this study will help plan a larger confirmatory trial for treating stroke-related dysphagia and advance our understanding of important covariates influencing swallowing recovery and response to the proposed intervention., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: Pneumonia is a morbid complication of stroke, but evidence-based strategies for its prevention are lacking. Acid-suppressive medications have been associated with increased risk for nosocomial pneumonia in hospitalized patients. It is unclear whether these results can be extrapolated to stroke patients, where other factors strongly modulate pneumonia risk. We investigated the association between acid-suppressive medication and hospital-acquired pneumonia in patients with acute stroke., Methods: All patients hospitalized with acute ischemic stroke or intracerebral hemorrhage in a large, urban academic medical center in Boston, Massachusetts from June 2000 to June 2010 who were ≥18 years of age and hospitalized for ≥2 days were eligible for inclusion. Acid-suppressive medication use was defined as any pharmacy charge for a proton-pump inhibitor or histamine-2 receptor antagonist. Multivariate logistic regression was used to control for confounders. The main outcome measure was hospital-acquired pneumonia, defined via International Classification of Diseases, Ninth Revision, Clinical Modification codes., Results: The cohort comprised 1,676 admissions. Acid-suppressive medication was ordered in 1,340 (80%) and hospital-acquired pneumonia occurred in 289 (17.2%). The unadjusted incidence of hospital-acquired pneumonia was higher in the group exposed to acid-suppressive medication compared to those unexposed (20.7% vs 3.6%, odds ratio [OR] = 7.0, 95% confidence interval [CI] = 3.9-12.7). After adjustment, the OR of hospital-acquired pneumonia in the exposed group was 2.3 (95% CI = 1.2-4.6). The association was significant for proton-pump inhibitors (OR = 2.7, 95% CI = 1.4-5.4), but not for histamine-2 receptor antagonists (OR = 1.6, 95% CI = 0.8-3.4)., Interpretation: In this large hospital-based cohort of patients presenting with acute stroke, acid-suppressive medication use was associated with increased odds of hospital-acquired pneumonia., (© 2014 American Neurological Association.)

Using a pre-post design, eleven chronic stroke patients with large left hemisphere lesions and nonfluent aphasia underwent diffusion tensor imaging and language testing before and after receiving 15 weeks of an intensive intonation-based speech therapy. This treated patient group was compared to an untreated patient group (n=9) scanned twice over a similar time period. Our results showed that the treated group, but not the untreated group, had reductions in fractional anisotropy in the white matter underlying the right inferior frontal gyrus (IFG, pars opercularis and pars triangularis), the right posterior superior temporal gyrus, and the right posterior cingulum. Furthermore, we found that greater improvements in speech production were associated with greater reductions in FA in the right IFG (pars opercularis). Thus, our findings showed that an intensive rehabilitation program for patients with nonfluent aphasia led to structural changes in the right hemisphere, which correlated with improvements in speech production., (Copyright © 2014 Elsevier Inc. All rights reserved.)

There is a need to identify biomarkers that predict degree of chronic speech fluency/language impairment and potential for improvement after stroke. We previously showed that the Arcuate Fasciculus lesion load (AF-LL), a combined variable of lesion site and size, predicted speech fluency in patients with chronic aphasia. In the current study, we compared lesion loads of such a structural map (i.e., AF-LL) with those of a functional map [i.e., the functional gray matter lesion load (fGM-LL)] in their ability to predict speech fluency and naming performance in a large group of patients. The fGM map was constructed from functional brain images acquired during an overt speaking task in a group of healthy elderly controls. The AF map was reconstructed from high-resolution diffusion tensor images also from a group of healthy elderly controls. In addition to these two canonical maps, a combined AF-fGM map was derived from summing fGM and AF maps. Each canonical map was overlaid with individual lesion masks of 50 chronic aphasic patients with varying degrees of impairment in speech production and fluency to calculate a functional and structural lesion load value for each patient, and to regress these values with measures of speech fluency and naming. We found that both AF-LL and fGM-LL independently predicted speech fluency and naming ability; however, AF lesion load explained most of the variance for both measures. The combined AF-fGM lesion load did not have a higher predictability than either AF-LL or fGM-LL alone. Clustering and classification methods confirmed that AF lesion load was best at stratifying patients into severe and non-severe outcome groups with 96% accuracy for speech fluency and 90% accuracy for naming. An AF-LL of greater than 4 cc was the critical threshold that determined poor fluency and naming outcomes, and constitutes the severe outcome group. Thus, surrogate markers of impairments have the potential to predict outcomes and can be used as a stratifier in experimental studies.

Using an adapted version of Melodic Intonation Therapy (MIT), we treated an adolescent girl with a very large left-hemisphere lesion and severe nonfluent aphasia secondary to an ischemic stroke. At the time of her initial assessment 15 months after her stroke, she had reached a plateau in her recovery despite intense and long-term traditional speech-language therapy (approximately five times per week for more than one year). Following an intensive course of treatment with our adapted form of MIT, her performance improved on both trained and untrained phrases, as well as on speech and language tasks. These behavioral improvements were accompanied by functional MRI changes in the right frontal lobe as well as by an increased volume of white matter pathways in the right hemisphere. No increase in white matter volume was seen in her healthy twin sister, who was scanned twice over the same time period. This case study not only provides further evidence for MIT's effectiveness, but also indicates that intensive treatment can induce functional and structural changes in a right-hemisphere fronto-temporal network., (© 2012 New York Academy of Sciences.)

Despite the fact that as many as 25% of the children diagnosed with autism spectrum disorders are nonverbal, surprisingly little research has been conducted on this population. In particular, the mechanisms that underlie their absence of speech remain unknown. Using diffusion tensor imaging, we compared the structure of a language-related white matter tract (the arcuate fasciculus, AF) in five completely nonverbal children with autism to that of typically developing children. We found that, as a group, the nonverbal children did not show the expected left-right AF asymmetry--rather, four of the five nonverbal children actually showed the reversed pattern. It is possible that this unusual pattern of asymmetry may underlie some of the severe language deficits commonly found in autism, particularly in children whose speech fails to develop. Furthermore, novel interventions (such as auditory-motor mapping training) designed to engage brain regions that are connected via the AF may have important clinical potential for facilitating expressive language in nonverbal children with autism., (© 2012 New York Academy of Sciences.)

Aphasia is a common symptom after left hemispheric stroke. Neuroimaging techniques over the last 10-15 years have described two general trends: Patients with small left hemisphere strokes tend to recruit perilesional areas, while patients with large left hemisphere lesions recruit mainly homotopic regions in the right hemisphere. Non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been employed to facilitate recovery by stimulating lesional and contralesional regions. The majority of these brain stimulation studies have attempted to block homotopic regions in the right posterior inferior frontal gyrus (IFG) to affect a presumed disinhibited right IFG (triangular portion). Other studies have used anodal or excitatory tDCS to stimulate the contralesional (right) fronto-temporal region or parts of the intact left IFG and perilesional regions to improve speech-motor output. It remains unclear whether the interhemispheric disinhibition model, which is the basis for motor cortex stimulation studies, also applies to the language system. Future studies could address a number of issues, including: the effect of lesion location on current density distribution, timing of the intervention with regard to stroke onset, whether brain stimulation should be combined with behavioral therapy, and whether multiple brain sites should be stimulated. A better understanding of the predictors of recovery from natural outcome studies would also help to inform study design, and the selection of clinically meaningful outcome measures in future studies.

Background and Purpose: Previous studies have suggested that patients' potential for poststroke language recovery is related to lesion size; however, lesion location may also be of importance, particularly when fiber tracts that are critical to the sensorimotor mapping of sounds for articulation (eg, the arcuate fasciculus) have been damaged. In this study, we tested the hypothesis that lesion loads of the arcuate fasciculus (ie, volume of arcuate fasciculus that is affected by a patient's lesion) and of 2 other tracts involved in language processing (the extreme capsule and the uncinate fasciculus) are inversely related to the severity of speech production impairments in patients with stroke with aphasia., Methods: Thirty patients with chronic stroke with residual impairments in speech production underwent high-resolution anatomic MRI and a battery of cognitive and language tests. Impairment was assessed using 3 functional measures of spontaneous speech (eg, rate, informativeness, and overall efficiency) as well as naming ability. To quantitatively analyze the relationship between impairment scores and lesion load along the 3 fiber tracts, we calculated tract-lesion overlap volumes for each patient using probabilistic maps of the tracts derived from diffusion tensor images of 10 age-matched healthy subjects., Results: Regression analyses showed that arcuate fasciculus lesion load, but not extreme capsule or uncinate fasciculus lesion load or overall lesion size, significantly predicted rate, informativeness, and overall efficiency of speech as well as naming ability., Conclusions: A new variable, arcuate fasciculus lesion load, complements established voxel-based lesion mapping techniques and, in the future, may potentially be used to estimate impairment and recovery potential after stroke and refine inclusion criteria for experimental rehabilitation programs.

It has been reported for more than 100 years that patients with severe nonfluent aphasia are better at singing lyrics than they are at speaking the same words. This observation led to the development of melodic intonation therapy (MIT). However, the efficacy of this therapy has yet to be substantiated in a randomized controlled trial. Furthermore, its underlying neural mechanisms remain unclear. The two unique components of MIT are the intonation of words and simple phrases using a melodic contour that follows the prosody of speech and the rhythmic tapping of the left hand that accompanies the production of each syllable and serves as a catalyst for fluency. Research has shown that both components are capable of engaging fronto-temporal regions in the right hemisphere, thereby making MIT particularly well suited for patients with large left hemisphere lesions who also suffer from nonfluent aphasia. Recovery from aphasia can happen in two ways: either through the recruitment of perilesional brain regions in the affected hemisphere, with variable recruitment of right-hemispheric regions if the lesion is small, or through the recruitment of homologous language and speech-motor regions in the unaffected hemisphere if the lesion of the affected hemisphere is extensive. Treatment-associated neural changes in patients undergoing MIT indicate that the unique engagement of right-hemispheric structures (e.g., the superior temporal lobe, primary sensorimotor, premotor and inferior frontal gyrus regions) and changes in the connections across these brain regions may be responsible for its therapeutic effect.

For more than 100 years, clinicians have noted that patients with nonfluent aphasia are capable of singing words that they cannot speak. Thus, the use of melody and rhythm has long been recommended for improving aphasic patients' fluency, but it was not until 1973 that a music-based treatment [Melodic Intonation Therapy (MIT)] was developed. Our ongoing investigation of MIT's efficacy has provided valuable insight into this therapy's effect on language recovery. Here we share those observations, our additions to the protocol that aim to enhance MIT's benefit, and the rationale that supports them.

Recovery from aphasia can be achieved through recruitment of either perilesional brain regions in the affected hemisphere or homologous language regions in the nonlesional hemisphere. For patients with large left-hemisphere lesions, recovery through the right hemisphere may be the only possible path. The right-hemisphere regions most likely to play a role in this recovery process are the superior temporal lobe (important for auditory feedback control), premotor regions/posterior inferior frontal gyrus (important for planning and sequencing of motor actions and for auditory-motor mapping), and the primary motor cortex (important for execution of vocal motor actions). These regions are connected reciprocally via a major fiber tract called the arcuate fasciculus (AF), however, this tract is not as well developed in the right hemisphere as it is in the dominant left. We tested whether an intonation-based speech therapy (i.e., melodic intonation therapy [MIT]), which is typically administered in an intense fashion with 75-80 daily therapy sessions, would lead to changes in white-matter tracts, particularly the AF. Using diffusion tensor imaging (DTI), we found a significant increase in the number of AF fibers and AF volume comparing post- with pretreatment assessments in six patients that could not be attributed to scan-to-scan variability. This suggests that intense, long-term MIT leads to remodeling of the right AF and may provide an explanation for the sustained therapy effects that were seen in these six patients.

It has been reported that patients with severely nonfluent aphasia are better at singing lyrics than speaking the same words. This observation inspired the development of Melodic Intonation Therapy (MIT), a treatment whose effects have been shown, but whose efficacy is unproven and neural correlates remain unidentified. Because of its potential to engage/unmask language-capable regions in the unaffected right hemisphere, MIT is particularly well suited for patients with large left-hemisphere lesions. Using two patients with similar impairments and stroke size/location, we show the effects of MIT and a control intervention. Both interventions' post-treatment outcomes revealed significant improvement in propositional speech that generalized to unpracticed words and phrases; however, the MIT-treated patient's gains surpassed those of the control-treated patient. Treatment-associated imaging changes indicate that MIT's unique engagement of the right hemisphere, both through singing and tapping with the left hand to prime the sensorimotor and premotor cortices for articulation, accounts for its effect over nonintoned speech therapy.

Background: Recent findings of a tight coupling between visual and auditory association cortices during multisensory perception in monkeys and humans raise the question whether consistent paired presentation of simple visual and auditory stimuli prompts conditioned responses in unimodal auditory regions or multimodal association cortex once visual stimuli are presented in isolation in a post-conditioning run. To address this issue fifteen healthy participants partook in a "silent" sparse temporal event-related fMRI study. In the first (visual control) habituation phase they were presented with briefly red flashing visual stimuli. In the second (auditory control) habituation phase they heard brief telephone ringing. In the third (conditioning) phase we coincidently presented the visual stimulus (CS) paired with the auditory stimulus (UCS). In the fourth phase participants either viewed flashes paired with the auditory stimulus (maintenance, CS-) or viewed the visual stimulus in isolation (extinction, CS+) according to a 5:10 partial reinforcement schedule. The participants had no other task than attending to the stimuli and indicating the end of each trial by pressing a button., Results: During unpaired visual presentations (preceding and following the paired presentation) we observed significant brain responses beyond primary visual cortex in the bilateral posterior auditory association cortex (planum temporale, planum parietale) and in the right superior temporal sulcus whereas the primary auditory regions were not involved. By contrast, the activity in auditory core regions was markedly larger when participants were presented with auditory stimuli., Conclusion: These results demonstrate involvement of multisensory and auditory association areas in perception of unimodal visual stimulation which may reflect the instantaneous forming of multisensory associations and cannot be attributed to sensation of an auditory event. More importantly, we are able to show that brain responses in multisensory cortices do not necessarily emerge from associative learning but even occur spontaneously to simple visual stimulation.