Abstract
Introduction
Predictors of long-term ischemic and hemorrhagic complications in atrial fibrillation (AF) have been studied, but there is limited data on predictors of early ischemic and hemorrhagic complications after AF associated ischemic stroke. We sought to determine these predictors.
Methods
The Initiation of Anticoagulation after Cardioembolic stroke (IAC) study is a multicenter retrospective study across that pooled data from consecutive patients with ischemic stroke in the setting of AF from stroke registries across 8 comprehensive stroke centers in the United States. The co-primary outcomes were recurrent ischemic event (stroke/TIA/systemic arterial embolism) and delayed symptomatic intracranial hemorrhage (d-sICH) within 90 days. We performed univariate analyses and cox regression analyses including important predictors on univariate analyses to determine independent predictors of early ischemic events (stroke/TIA/systemic embolism) and d-sICH.
Results
Out of 2084 patients, 1520 patients qualified; 104 patients (6.8%) had recurrent ischemic events and 23 patients (1.5%) had d-sICH within 90 days from the index event. In cox-regression models, factors associated with a trend for recurrent ischemic events were prior stroke or TIA (HR 1.42, 0.96 – 2.10) and ipsilateral arterial stenosis with 50–99% narrowing (HR 1.54, 0.98 – 2.43). Those associated with sICH were female sex (HR 2.68, 1.06– 6.83), history of hyperlipidemia (HR 2.91, 1.08 – 7.84), and early hemorrhagic transformation (HR 5.35, 2.22 – 12.92).
Conclusion
In patients with ischemic stroke and AF, predictors of d-sICH are different than those of recurrent ischemic events therefore recognizing these predictors may help inform early stroke versus d-sICH prevention strategies.
Keywords: Stroke, Atrial Fibrillation, Recurrence, Anticoagulation, Predictors
Introduction
Cardioembolic stroke in patients with atrial fibrillation (AF) is associated with high mortality and morbidity1, carrying a relatively high risk of early ischemic recurrence and hemorrhagic transformation.2,3 Initiating anticoagulation acutely after a cardioembolic stroke is typically avoided due to the risk of early hemorrhagic complications and current guidelines suggest starting anticoagulation in the 4–14 day interval after the index stroke.4
Predictors of long term ischemic and hemorrhagic complications in patients with AF have been extensively studied,5 but there is very limited data on predictors of early ischemic and hemorrhagic complications after an AF-associated cardioembolic stroke.6 Determining these predictors may help clinicians individualize treatments based on differential ischemic and hemorrhagic risks, and may help determine the optimal timing of initiation of anticoagulation based on their early hemorrhagic and ischemic risk.
In this study, we sought to determine clinical, laboratory, and imaging predictors of early ischemic and non-acute therapy related hemorrhagic events in patients with ischemic stroke in the setting of AF.
Methods
Study cohort
Institutional Review Board approval was obtained from each of the participating centers. The Initiation of Anticoagulation after Cardioembolic stroke (IAC) study is a multicenter study across that pooled data from stroke registries across 8 comprehensive stroke centers in the United States. Consecutive patients hospitalized with acute ischemic stroke in the setting of AF (history of AF or AF diagnosed on admission) were included. Patient who developed AF after the index hospitalization were excluded. In addition, patients with competing stroke mechanisms were included in our study consistent with the main goal of the IAC study which sought to determine the optimal timing of initiating anticoagulation and because these patients would typically be treated with anticoagulation for secondary prevention regardless of the primary stroke mechanism.
Study variables
The following study variables were collected:
Demographic factors:
Age and Sex
Clinical variables:
Time from onset to hospital arrival, comorbidities (hypertension, diabetes, hyperlipidemia, prior stroke or TIA, congestive heart failure, coronary artery disease, peripheral vascular disease, smoking, CHA2DS2-Vasc score), NIHSS score, and systolic and diastolic blood pressures on admission.
Medications prior to admission:
Antiplatelet use, anticoagulant use, and statin use.
Laboratory values on admission:
Glucose level, platelet count, and low density lipoprotein
Neuroimaging and vascular imaging variables:
Presence of intracranial or extracranial atherosclerosis with ≥ 50% luminal narrowing in the territory of the stroke, location of stroke (anterior circulation vs. posterior circulation), largest ischemic stroke lesion volume (moderate to large defined as > 10 mL), and early hemorrhagic transformation in the setting of acute therapy occurring within 48 hours from index event.7,8
Echocardiographic variables:
Left atrial enlargement (determined by left atrial diameter, volume, index, or volume-index)9, moderate to severe aortic or mitral valve heart disease, bioprosthetic valve, intracranial thrombus, spontaneous echocardiographic contrast, and ejection fraction.
In-hospital treatments:
Alteplase and mechanical thrombectomy, anticoagulation initiation and time to initiate anticoagulation.
Outcomes
The study co-primary outcomes were recurrent ischemic event (stroke/TIA/systemic arterial embolism) and d-sICH within 90 days. D-sICH was defined as neurological deterioration in the setting of any new or worsening hemorrhage and the hemorrhage being the cause of the neurological deterioration.7 Early hemorrhagic transformation related to acute stroke therapy was not considered as outcome but these patients were still included in the analysis.
In all participating centers, patients discharged with a diagnosis of stroke were scheduled to have an in-person clinic visit at 90 days. In addition, in 3 out of 8 centers, pre-specified phone calls were performed at the 30-day (in one center) and 90-day (in two centers) time points that assessed for recurrent ischemic and hemorrhagic outcomes. Outcomes were preferentially abstracted from the 90-day patient follow up visit and pre-specified 90-day phone calls. In the sites assessing 90-day outcomes by phone and for patients not showing up to their 90 day visits, three attempts were made on different occasions to contact the patient or health care provider by phone. If unsuccessful, then outcomes were assessed by chart review of hospitalization and other outpatient visit and outside hospital records. All outcomes were abstracted by the study local research assistant and confirmed by the site principal investigator. Multiple queries were sent to the participating sites regarding study outcomes and other variables in our dataset and several data cross-checks were performed to confirm the integrity of the data sent by individual sites.
Analytical plan
Data from sites was pooled and queries were sent to assure accuracy of data, as indicated. We excluded patients that were lost to follow up as well as those who did not experience the study outcome of interest but died within 90 days. We stratified patients based on the occurrence of the co-primary outcomes (recurrent ischemic events or d-sICH) and compared the rates of the respective primary outcomes across the above-mentioned study variables. We then performed cox regression analyses including important predictors found on univariate analyses to determine independent predictors of early ischemic events and d-sICH, respectively. Analyses were done using SPSS version 25.0 (Chicago, IL).
Results
We enrolled 2,084 patients into the parent study. Of these, 564 patients were excluded due to: 195 lost to follow up and 369 died within 90 days without having a study outcome. The final sample included 1,520 patients; median age was 78 years (68–86) and 50.1% (762/1520) were men. Among the included patients, 104 patients (6.8%) had recurrent ischemic events (91 patients with recurrent stroke, 6 patients with TIA, and 9 patients with systemic embolism) and 23 patients (1.5%) had a d-sICH within 90 days from the index event (Figure 1).
Figure 1:
Study flow chart
Univariate analyses
In univariate analyses patients with recurrent ischemic events were more likely to have a history of prior stroke or TIA (39.4% vs. 30.7%, p = 0.079) and ipsilateral arterial stenosis with 50–99% narrowing (23.1% vs. 15.9%, p = 0.073) as compared to patients without recurrent events. Other clinical, laboratory, and radiographic variables did not differ significantly between groups (Table 1).
Table 1.
Univariate analyses of predictors of recurrent ischemic events
| No ischemic events (n = 1416) | Ischemic events (n = 104) | p-value | |
|---|---|---|---|
| Age (median, IQR) | 78 (17) | 76 (18) | 0.179 |
| Sex (% male) | 706 (49.9%) | 56 (53.8%) | 0.477 |
| Hypertension (%) | 1175/1415 (83.0%) | 82 (78.8%) | 0.282 |
| Diabetes (%) | 474/1414 (33.5%) | 36 (34.6%) | 0.830 |
| Hyperlipidemia (%) | 795/1415 (56.2%) | 58 (55.8%) | 1.000 |
| Prior Stroke or TIA (%) | 435/1415 (30.7%) | 41 (39.4%) | 0.079 |
| Active smoking (%) | 170/1414 (12.0%) | 13 (12.5%) | 0.876 |
| Congestive heart failure (%) | 346/1393 (24.8%) | 25 (24.0%) | 0.907 |
| Coronary artery disease (%) | 440/1415 (31.1%) | 36 (34.6%) | 0.446 |
| Peripheral vascular disease (%) | 93/1414 (6.6%) | 7 (6.7%) | 0.840 |
| CHA2DS2-Vasc score (median, IQR) | 5 (3) | 5 (3) | 0.215 |
| AF type paroxysmal (%) | 687/1337 (51.4%) | 49/94 (52.1%) | 0.915 |
| Home anticoagulation (%) | 502/1414 (35.5%) | 44 (42.3%) | 0.170 |
| Systolic blood pressure (median, IQR) | 148 (34) | 152 (37) | 0.275 |
| Diastolic blood pressure (median, IQR) | 80 (22) | 80 (21) | 0.929 |
| NIHSS score (median, IQR) | 8 (12) | 8 (12) | 0.767 |
| Glucose (median, IQR) | 121 (45) | 125 (41) | 0.609 |
| LDL (median, IQR) | 77 (44) | 78 (33) | 0.951 |
| Positive troponin (%) | 151/1094 (13.8%) | 14/80 (17.5%) | 0.403 |
| Alteplase (%) | 412/1416 (29.1%) | 25 (24.0%) | 0.313 |
| Thrombectomy (%) | 358/1416 (25.2%) | 27 (25.9%) | 0.907 |
| Ischemic stroke ≥ 10 mL (%) | 770/1308 (58.9%) | 57/95 (60.0%) | 0.914 |
| Cardiac thrombus (%) | 18/1336 (1.3%) | 1/95 (1.1%) | 1.000 |
| Moderate to severe mitral stenosis (%) | 23/1337 (1.7%) | 3/95 (3.2%) | 0.246 |
| Severe left atrial enlargement (%) | 437/1154 (37.9%) | 31/78 (39.7%) | 0.810 |
| Left atrial volume (median, IQR) | 75 (41) | 72 (47) | 0.971 |
| Ipsilateral atherosclerosis 50% or more (%) | 221/1389 (15.9%) | 24 (23.1%) | 0.073 |
| Ejection fraction (median, IQR) | 59 (15) | 60 (11) | 0.652 |
| Anticoagulation initiated (%) | 1213/1412 (85.9%) | 87 (83.7%) | 0.562 |
| Time to initiating anticoagulation (median, IQR) | 4 (8) | 3 (8) | 0.358 |
When compared to subjects without d-sICH, patients with d-sICH were more likely to be women (73.9% vs. 49.5%, p = 0.021), have hyperlipidemia (78.3% vs. 55.8%, p = 0.034), a largest ischemic lesion size > 10 mL (82.6% vs. 58.5%, p = 0.019), and early hemorrhagic transformation (60.9% vs. 17.0%, p<0.001) (Table 2).
Table 2.
Univariate analyses of predictors of delayed symptomatic intracranial hemorrhage (d-sICH)
| No d-sICH (n = 1497) | d-sICH (n = 23) | p-value | |
|---|---|---|---|
| Age (median, IQR) | 78 (18) | 72 (15) | 0.081 |
| Sex (% male) | 756 (50.5%) | 6 (26.1%) | 0.021 |
| Hypertension (%) | 1239/1496 (82.8%) | 18 (78.3%) | 0.577 |
| Diabetes (%) | 499/1495 (33.4%) | 11 (47.8%) | 0.181 |
| Hyperlipidemia (%) | 835/1496 (55.8%) | 18 (78.3%) | 0.034 |
| Prior Stroke or TIA (%) | 471/1496 (31.5%) | 5 (21.7%) | 0.373 |
| Active smoking (%) | 179/1495 (12.0%) | 4 (17.4%) | 0.605 |
| Congestive heart failure (%) | 364/1474 (24.7%) | 7 (30.4%) | 0.477 |
| Coronary artery disease (%) | 466/1496 (31.1%) | 10 (43.5%) | 0.256 |
| Peripheral vascular disease (5) | 99/1495 (6.6%) | 1 (4.4%) | 1.000 |
| CHA2DS2Vasc score (median, IQR) | 5 (3) | 4 (4) | 0.876 |
| Home statin (%) | 817/1495 (54.6%) | 17 (73.9%) | 0.090 |
| Home anticoagulation (%) | 537/1495 (35.9%) | 9 (39.1%) | 0.827 |
| Systolic blood pressure (median, IQR) | 148 (34) | 143 (28) | 0.099 |
| Diastolic blood pressure (median, IQR) | 80 (21) | 79 (20) | 0.813 |
| NIHSS score (median, IQR) | 8 (12) | 16 (14) | 0.073 |
| Glucose (median, IQR) | 121 (45) | 129 (70) | 0.962 |
| Low density lipoprotein (median, IQR) | 77 (44) | 75 (36) | 0.889 |
| Platelet count (median, IQR) | 205 (84) | 204 (77) | 0.964 |
| Alteplase (%) | 434 (29.0%) | 3 (13.0%) | 0.107 |
| Thrombectomy (%) | 377 (25.2%) | 8 (34.8%) | 0.333 |
| Ischemic stroke > 10 mL (%) | 808/1380 (57.9%) | 19 (82.6%) | 0.019 |
| Posterior circulation location (%) | 251/1429 (17.6%) | 5 (21.7%) | 0.582 |
| Early hemorrhagic transformation (%) | 255/1497 (17.0%) | 14 (60.9%) | <0.001 |
| Anticoagulation initiated (%) | 1278/1493 (85.6%) | 22 (95.7%) | 0.235 |
| Time to initiating anticoagulation (median, IQR) | 4 (8) | 6 (13) | 0.133 |
Multivariable models for variables associated with recurrent ischemic events
In cox regression models, factors with a trend for increased odds of recurrent ischemic events were prior stroke and TIA (adjusted HR 1.42 95% CI 0.96 – 2.10, p = 0.082) and ipsilateral arterial stenosis with 50–99% narrowing (adjusted OR 1.54 95% CI 0.98 – 2.43, p = 0.063) (Table 3). Survival analyses of these predictors are shown in Figure 2.
Table 3.
Cox regression model showing predictors of ischemic events
| Unadjusted (HR 95% CI, p-value) |
Adjusted* (HR 95% CI, p-value) |
|
|---|---|---|
| Prior stroke or TIA | 1.44 (0.97 – 2.14) , p = 0.071 | 1.42 (0.96 – 2.10), p = 0.082 |
| Ipsilateral atherosclerosis | 1.56 (0.99 – 2.46), p = 0.068 | 1.54 (0.98 – 2.43), p = 0.063 |
adjusted for prior stroke and ipsilateral atherosclerosis
Figure 2:
Kaplan- Meier survival analysis showing predictors of recurrent ischemic events stratified by A. Prior stroke or TIA and B. Ipsilateral Atherosclerosis with 50–99% luminal narrowing
Multivariable models for variables associated with sICH
In cox regression models, factors associated with d-sICH were female gender (adjusted HR 2.68 95% CI 1.06– 6.83, p = 0.038), history of hyperlipidemia (adjusted HR 2.91 95% CI 1.08 – 7.84, p = 0.035), and early hemorrhagic transformation (HR 5.35 95% CI 2.22 – 12.92, p<0.001) (Table 4). Sensitivity analyses adding age to the cox-regression model showed no significant associations between age and d-sICH (adjusted HR 0.98 95% CI 0.95 – 1.02, p = 0.338) and the rest of the associations remained unchanged (Table 4). Survival analyses of these predictors are shown in Figure 3.
Table 4.
Cox regression models of predictors of symptomatic intracranial hemorrhage
| Unadjusted HR 95% CI, p-value |
Adjusted* HR 95% CI, p-value |
Adjusted** HR 95% CI, p-value |
|
|---|---|---|---|
| Woman sex | 2.88 (1.13 – 7.29) p = 0.026 |
2.68 (1.06– 6.83) p = 0.038 |
2.44 (0.94 – 6.33) p = 0.067 |
| Hyperlipidemia | 2.83 (1.05 – 7.62) p = 0.040 |
2.91 (1.08 – 7.84) p = 0.035 |
2.97 (1.10 – 8.01) p = 0.032 |
| Ischemic lesion > 10 mL | 3.34 (1.14 – 9.81) p = 0.029 |
1.94 (0.62 – 6.04) p = 0.253 |
1.88 (0.60 – 5.87) p = 0.277 |
| Early hemorrhagic transformation | 7.37 (3.19 – 17.04 p<0.001 |
5.35 (2.22 – 12.92) p<0.001 |
5.35 (2.21 – 12.90) p < 0.001 |
adjusted for woman sex, history of hyperlipidemia, ischemic lesion > 10 mL, and early hemorrhagic transformation.
adjusted for age, woman sex, history of hyperlipidemia, ischemic lesion > 10 mL, and early hemorrhagic transformation.
Figure 3:
Kaplan- Meier survival analysis showing predictors of delayed symptomatic intracranial hemorrhage (sICH) stratified by A. Sex, B. History of Hyperlipidemia, and C. Presence of early hemorrhagic transformation
Additional analysis
We performed additional analyses to better understand the association between hyperlipidemia and d-sICH. In these analyses, when compared to patients without a history of hyperlipidemia, those with hyperlipidemia were more likely to be on statins (68.7% vs. 37.4%, p < 0.001). In addition, the median (IQR) LDL was lower in those with a history of hyperlipidemia versus those without [75 (42) vs. 80 (43), p = 0.004]. This suggests increased usage of statins and lower LDL cholesterols in those with versus without history of hyperlipidemia.
Moreover, given that ipsilateral atherosclerosis may be more associated with recurrent ischemic stroke or TIA, we performed additional analysis looking at the association between these two. In these analyses, there was significant association between ipsilateral atherosclerosis causing 50% or more arterial narrowing and recurrent ischemic stroke or TIA (9.4% vs. 5.8%, p = 0.044).
Discussion
In this large multicenter study, we identified predictors of early recurrent ischemic events and d-sICH in patients with cardioembolic stroke in the setting of AF. Factors with a trend for increased odds of recurrent ischemic events were history of ischemic stroke or TIA and large artery stenosis causing 50% or more arterial narrowing supplying the territory of the infarct. Important predictors of d-sICH were early hemorrhagic transformation, female sex, and known history of hyperlipidemia.
Mechanisms of Associations
Several studies have shown that ipsilateral arterial stenosis is an important predictor of early recurrence in non-cardioembolic stroke via several mechanisms including artery to artery embolization and infarct growth in the setting of branch atheromatous disease or hypoperfusion.10–13 Although this association has not been investigated in patients with ischemic stroke in the setting of AF, it is likely that in some of our patients, particularly those with ipsilateral atherosclerosis causing 50% or more luminal narrowing, the mechanism of stroke may have been related to large artery atherosclerotic disease as opposed to AF, which among stroke subtypes, portends a higher risk of early recurrence.10 This is likely a specific predictor of recurrent ischemic stroke or TIA as shown in our study. In addition, in patients with AF, prior stroke or TIA is the most important predictor of long term ischemic stroke risk.5,14 These studies, however, did not investigate the effect of prior stroke on early recurrence and therefore more studies are needed to confirm this association. Furthermore, in our study, the CHA2DS2-Vasc score was not an important predictor of early recurrence. This observation is in line with prior studies in AF6 as well as in non-AF patients where the risk of early recurrence is likely related to the specific underlying stroke mechanism, which may not be adequately captured by clinical scores that are based on the cumulative vascular risk factors and that do not consider the quality of stroke prevention measures in affected patients.10 Furthermore, in our study serum and echocardiographic factors were not associated with early ischemic stroke recurrence. For instance, unlike prior observations6, severe left atrial enlargement and spontaneous echocardiographic contrast on echocardiography did not portend an increased risk of early recurrence in our study. Although this may be the case, it is also possible that echocardiographic findings may have led treating physicians to pursue more aggressive strategies leading to a reduction in early recurrence risk. In addition, transthoracic echocardiography, the main modality used to assess cardiac structure and function in our study, is limited in the assessment of left atrial and left atrial appendage pathology. Thus, we may have underestimated the presence of such atrial pathology and this finding needs further study.
The second important observation from our study was the identification of several predictors of d-sICH. The identified risk factors have been shown to relate to several, not mutually exclusive mechanisms implicated in the formation of sICH, including early disruption of the blood brain barrier, coagulopathy, and reperfusion injury.7,8 Specifically, markers of blood brain barrier dysfunction such as early hemorrhagic transformation were important predictors of d-sICH. In addition, the association between history of hyperlipidemia and d-sICH is noteworthy. In our cohort, patients with a history of hyperlipidemia were more likely to be on statin therapy and had significantly lower LDL levels than those without a history of hyperlipidemia. Therefore, it is possible that the association between history of hyperlipidemia and d-sICH may be at least partially mediated by statin use. Randomized controlled trials showed that statin therapy was associated with increased risk of ICH15,16 and some hypothesize that it may be related to effect of statins on the integrity of the neurovascular unit, predisposing to “leakage” and posing increased risk of hemorrhagic complications.17 In patients with ischemic stroke receiving altepalse, there is mixed evidence on the short term benefit of statins. For instance, while one study shows that pretreatment with statins was not associated with increased hemorrhagic complications18–20, others show increased risk of sICH with statin therapy21, particularly when higher doses are used.22 It is therefore possible that while in most patients statin use may provide both short-term and long term benefit23, it may increase the risk of hemorrhagic complications in a subset of patients and in these patients, the benefit of high intensity therapy should be weighed against the risk of hemorrhagic complications. Furthermore, in our study, female sex was associated with increased hemorrhagic complications. Prior studies showed that women with acute ischemic stroke are more likely to have worse compared outcomes to men24,25 and one studies reports higher rates of sICH with women.26 This association has not been confirmed in other studies including a meta-analysis25 and therefore our finding needs to be confirmed. To note that we did not include NIHSS score in the adjusted model because it correlated with ischemic stroke volume which was included in the cox-regression model.
Clinical Implications
Our study has several clinical implications. First, it is reassuring to see that the risk of early recurrence and d-sICH in patients with AF related ischemic stroke was fairly low. In fact, our risk estimates were lower than what has been previously reported,2,3 which provides evidence on the importance of current stroke prevention strategies to reduce this risk. Second, predictors of early recurrent ischemic events were different from those of d-sICH, which is important for clinicians as those at high risk of recurrent ischemic event are not necessarily at a higher risk of d-sICH. Therefore, identifying these predictors would help clinicians balance the risk of recurrent stroke against symptomatic hemorrhage when deciding on recurrent stroke vs. d-sICH prevention strategies. Third, the association between ipsilateral arterial stenosis with early recurrence risk highlights the importance of vascular imaging in patients with AF to determine potential competing mechanism that portends a high risk of early recurrence. This is particularly important in patients with cervical ICA stenosis, a group who may benefit from carotid revascularization27 and in those with intracranial stenosis who may benefit from antiplatelet therapy and high intensity stating therapy.27–29 While some studies show that echocardiography in patients with known mechanism may be useful to diagnose clinically covert cardiovascular disease30, in our study the lack of association between echocardiographic variables and early recurrence challenges the role of routine echocardiography use to risk stratify patients with ischemic stroke and known AF, which is line with current guidelines.4 Finally, the association between history of hyperlipidemia and d-sICH and the possibility of this to be at least partially mediated by statins warrants further investigation, particularly in those at higher risk of d-sICH and low LDL levels.
Strengths and limitations
Our study has several limitations including its retrospective nature and involving patients treated at comprehensive stroke centers, potentially introducing bias that may reduce generalizability of our findings to smaller community hospitals. In addition, we lack data on several factors including treatments such as carotid intervention and medication dosages and medication adherence which may influence stroke and hemorrhage risk. Furthermore, imaging and echocardiographic were performed for clinical use and techniques may have varied across centers which may have added heterogeneity. Moreover, the small number of d-sICH outcomes reduced the power of our statistical analyses. Finally, since our study was not randomized, the usual clinical practice could impact the risk of ischemic or hemorrhagic recurrence; for example delaying anticoagulation in patients with hemorrhagic transformation. Major strengths or our study relate to the inclusion of a large, well characterized patient cohort with the use of real world data, including pertinent clinical, laboratory, imaging, and echocardiographic variables not considered in previous studies. In addition, our study included patients treated across 8 centers in the United States with variability in practice and therefore may offer a good representation of the real world practices when treating ischemic stroke in the setting of AF.
Conclusion
In patients with ischemic stroke in the setting of AF, predictors of d-sICH differ from those of recurrent ischemic events. Identifying, and differentially considering these predictors may aid risk stratification of patients and inform early stroke and d-sICH prevention strategies. Due to our study limitations, larger prospective studies are needed to confirm our findings.
Disclosures:
Dr. Henninger is supported by K08NS091499 from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and R44NS076272 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Liberman is supported by K23NS107643 from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. All other authors report no disclosures or acknowledgments.
Footnotes
Disclosures: None
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