Publications by Year: 2015

Schaefer PW, Pulli B, Copen WA, Hirsch JA, Leslie-Mazwi T, Schwamm LH, Wu O, González RG, Yoo AJ. Combining MRI with NIHSS thresholds to predict outcome in acute ischemic stroke: value for patient selection. AJNR Am J Neuroradiol 2015;36(2):259-64.Abstract
BACKGROUND AND PURPOSE: Selecting acute ischemic stroke patients for reperfusion therapy on the basis of a diffusion-perfusion mismatch has not been uniformly proved to predict a beneficial treatment response. In a prior study, we have shown that combining clinical with MR imaging thresholds can predict clinical outcome with high positive predictive value. In this study, we sought to validate this predictive model in a larger patient cohort and evaluate the effects of reperfusion therapy and stroke side. MATERIALS AND METHODS: One hundred twenty-three consecutive patients with anterior circulation acute ischemic stroke underwent MR imaging within 6 hours of stroke onset. DWI and PWI volumes were measured. Lesion volume and NIHSS score thresholds were used in models predicting good 3-month clinical outcome (mRS 0-2). Patients were stratified by treatment and stroke side. RESULTS: Receiver operating characteristic analysis demonstrated 95.6% and 100% specificity for DWI > 70 mL and NIHSS score > 20 to predict poor outcome, and 92.7% and 91.3% specificity for PWI (mean transit time) < 50 mL and NIHSS score < 8 to predict good outcome. Combining clinical and imaging thresholds led to an 88.8% (71/80) positive predictive value with a 65.0% (80/123) prognostic yield. One hundred percent specific thresholds for DWI (103 versus 31 mL) and NIHSS score (20 versus 17) to predict poor outcome were significantly higher in treated (intravenous and/or intra-arterial) versus untreated patients. Prognostic yield was lower in right- versus left-sided strokes for all thresholds (10.4%-20.7% versus 16.9%-40.0%). Patients with right-sided strokes had higher 100% specific DWI (103.1 versus 74.8 mL) thresholds for poor outcome, and the positive predictive value was lower. CONCLUSIONS: Our predictive model is validated in a much larger patient cohort. Outcome may be predicted in up to two-thirds of patients, and thresholds are affected by stroke side and reperfusion therapy.
Chu CJ, Tanaka N, Diaz J, Edlow BL, Wu O, Hämäläinen M, Stufflebeam S, Cash SS, Kramer MA. EEG functional connectivity is partially predicted by underlying white matter connectivity. Neuroimage 2015;108:23-33.Abstract
Over the past decade, networks have become a leading model to illustrate both the anatomical relationships (structural networks) and the coupling of dynamic physiology (functional networks) linking separate brain regions. The relationship between these two levels of description remains incompletely understood and an area of intense research interest. In particular, it is unclear how cortical currents relate to underlying brain structural architecture. In addition, although theory suggests that brain communication is highly frequency dependent, how structural connections influence overlying functional connectivity in different frequency bands has not been previously explored. Here we relate functional networks inferred from statistical associations between source imaging of EEG activity and underlying cortico-cortical structural brain connectivity determined by probabilistic white matter tractography. We evaluate spontaneous fluctuating cortical brain activity over a long time scale (minutes) and relate inferred functional networks to underlying structural connectivity for broadband signals, as well as in seven distinct frequency bands. We find that cortical networks derived from source EEG estimates partially reflect both direct and indirect underlying white matter connectivity in all frequency bands evaluated. In addition, we find that when structural support is absent, functional connectivity is significantly reduced for high frequency bands compared to low frequency bands. The association between cortical currents and underlying white matter connectivity highlights the obligatory interdependence of functional and structural networks in the human brain. The increased dependence on structural support for the coupling of higher frequency brain rhythms provides new evidence for how underlying anatomy directly shapes emergent brain dynamics at fast time scales.
Copen WA, Deipolyi AR, Schaefer PW, Schwamm LH, González RG, Wu O. Exposing hidden truncation-related errors in acute stroke perfusion imaging. AJNR Am J Neuroradiol 2015;36(4):638-45.Abstract
BACKGROUND AND PURPOSE: The durations of acute ischemic stroke patients' CT or MR perfusion scans may be too short to fully sample the passage of the injected contrast agent through the brain. We tested the potential magnitude of hidden errors related to the truncation of data by short perfusion scans. MATERIALS AND METHODS: Fifty-seven patients with acute ischemic stroke underwent perfusion MR imaging within 12 hours of symptom onset, using a relatively long scan duration (110 seconds). Shorter scan durations (39.5-108.5 seconds) were simulated by progressively deleting the last-acquired images. CBV, CBF, MTT, and time to response function maximum (Tmax) were measured within DWI-identified acute infarcts, with commonly used postprocessing algorithms. All measurements except Tmax were normalized by dividing by the contralateral hemisphere values. The effects of the scan duration on these hemodynamic measurements and on the volumes of lesions with Tmax of >6 seconds were tested using regression. RESULTS: Decreasing scan duration from 110 seconds to 40 seconds falsely reduced perfusion estimates by 47.6%-64.2% of normal for CBV, 1.96%-4.10% for CBF, 133%-205% for MTT, and 6.2-8.0 seconds for Tmax, depending on the postprocessing method. This truncation falsely reduced estimated Tmax lesion volume by 71.5 or 93.8 mL, depending on the deconvolution method. "Lesion reversal" (ie, change from above-normal to apparently normal, or from >6 seconds to ≤6 seconds for the time to response function maximum) with increasing truncation occurred in 37%-46% of lesions for CBV, 2%-4% for CBF, 28%-54% for MTT, and 42%-44% for Tmax, depending on the postprocessing method. CONCLUSIONS: Hidden truncation-related errors in perfusion images may be large enough to alter patient management or affect outcomes of clinical trials.
Copen WA, Morais LT, Wu O, Schwamm LH, Schaefer PW, González GR, Yoo AJ. In Acute Stroke, Can CT Perfusion-Derived Cerebral Blood Volume Maps Substitute for Diffusion-Weighted Imaging in Identifying the Ischemic Core?. PLoS One 2015;10(7):e0133566.Abstract
BACKGROUND AND PURPOSE: In the treatment of patients with suspected acute ischemic stroke, increasing evidence suggests the importance of measuring the volume of the irreversibly injured "ischemic core." The gold standard method for doing this in the clinical setting is diffusion-weighted magnetic resonance imaging (DWI), but many authors suggest that maps of regional cerebral blood volume (CBV) derived from computed tomography perfusion imaging (CTP) can substitute for DWI. We sought to determine whether DWI and CTP-derived CBV maps are equivalent in measuring core volume. METHODS: 58 patients with suspected stroke underwent CTP and DWI within 6 hours of symptom onset. We measured low-CBV lesion volumes using three methods: "objective absolute," i.e. the volume of tissue with CBV below each of six published absolute thresholds (0.9-2.5 mL/100 g), "objective relative," whose six thresholds (51%-60%) were fractions of mean contralateral CBV, and "subjective," in which two radiologists (R1, R2) outlined lesions subjectively. We assessed the sensitivity and specificity of each method, threshold, and radiologist in detecting infarction, and the degree to which each over- or underestimated the DWI core volume. Additionally, in the subset of 32 patients for whom follow-up CT or MRI was available, we measured the proportion of CBV- or DWI-defined core lesions that exceeded the follow-up infarct volume, and the maximum amount by which this occurred. RESULTS: DWI was positive in 72% (42/58) of patients. CBV maps' sensitivity/specificity in identifying DWI-positive patients were 100%/0% for both objective methods with all thresholds, 43%/94% for R1, and 83%/44% for R2. Mean core overestimation was 156-699 mL for objective absolute thresholds, and 127-200 mL for objective relative thresholds. For R1 and R2, respectively, mean±SD subjective overestimation were -11±26 mL and -11±23 mL, but subjective volumes differed from DWI volumes by up to 117 and 124 mL in individual patients. Inter-rater agreement regarding the presence of infarction on CBV maps was poor (kappa = 0.21). Core lesions defined by the six objective absolute CBV thresholds exceeded follow-up infarct volumes for 81%-100% of patients, by up to 430-1002 mL. Core estimates produced by objective relative thresholds exceeded follow-up volumes in 91% of patients, by up to 210-280 mL. Subjective lesions defined by R1 and R2 exceeded follow-up volumes in 18% and 26% of cases, by up to 71 and 15 mL, respectively. Only 1 of 23 DWI lesions (4%) exceeded final infarct volume, by 3 mL. CONCLUSION: CTP-derived CBV maps cannot reliably substitute for DWI in measuring core volume, or even establish which patients have DWI lesions.
Wintermark M, Luby M, Bornstein NM, Demchuk A, Fiehler J, Kudo K, Lees KR, Liebeskind DS, Michel P, Nogueira RG, Parsons MW, Sasaki M, Wardlaw JM, Wu O, Zhang W, Zhu G, Warach SJ. International survey of acute stroke imaging used to make revascularization treatment decisions. Int J Stroke 2015;10(5):759-62.Abstract
BACKGROUND: To assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging. METHODS: STroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and the above mentioned societies. RESULTS: We received responses from 223 centers (2 from Africa, 38 from Asia, 10 from Australia, 101 from Europe, 4 from Middle East, 55 from North America, 13 from South America). In combination, the sites surveyed administered acute revascularization therapy to a total of 25,326 acute stroke patients in 2012. Seventy-three percent of these patients received intravenous (i.v.) tissue plasminogen activator (tPA), and 27%, endovascular therapy. Vascular imaging was routinely obtained in 79% (152/193) of sites for endovascular therapy decisions, and also as part of standard IV tPA treatment decisions at 46% (92/198) of sites. Modality, availability and use of acute vascular and perfusion imaging before revascularization varied substantially between geographical areas. The main obstacles to participate in randomized trials involving multimodal imaging included: mainly insufficient research support and staff (50%, 79/158) and infrequent use of multimodal imaging (27%, 43/158) . CONCLUSION: There were significant variations among sites and geographical areas in terms of stroke imaging work-up used tomake decisions both for intravenous and endovascular revascularization. Clinical trials using advanced imaging as a selection tool for acute revascularization therapy should address the need for additional resources and technical support, and take into consideration the lack of routine use of such techniques in trial planning.
Bouts MJRJ, Westmoreland SV, de Crespigny AJ, Liu Y, Vangel M, Dijkhuizen RM, Wu O, D'Arceuil HE. Magnetic resonance imaging-based cerebral tissue classification reveals distinct spatiotemporal patterns of changes after stroke in non-human primates. BMC Neurosci 2015;16:91.Abstract
BACKGROUND: Spatial and temporal changes in brain tissue after acute ischemic stroke are still poorly understood. Aims of this study were three-fold: (1) to determine unique temporal magnetic resonance imaging (MRI) patterns at the acute, subacute and chronic stages after stroke in macaques by combining quantitative T2 and diffusion MRI indices into MRI 'tissue signatures', (2) to evaluate temporal differences in these signatures between transient (n = 2) and permanent (n = 2) middle cerebral artery occlusion, and (3) to correlate histopathology findings in the chronic stroke period to the acute and subacute MRI derived tissue signatures. RESULTS: An improved iterative self-organizing data analysis algorithm was used to combine T2, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) maps across seven successive timepoints (1, 2, 3, 24, 72, 144, 240 h) which revealed five temporal MRI signatures, that were different from the normal tissue pattern (P < 0.001). The distribution of signatures between brains with permanent and transient occlusions varied significantly between groups (P < 0.001). Qualitative comparisons with histopathology revealed that these signatures represented regions with different histopathology. Two signatures identified areas of progressive injury marked by severe necrosis and the presence of gitter cells. Another signature identified less severe but pronounced neuronal and axonal degeneration, while the other signatures depicted tissue remodeling with vascular proliferation and astrogliosis. CONCLUSION: These exploratory results demonstrate the potential of temporally and spatially combined voxel-based methods to generate tissue signatures that may correlate with distinct histopathological features. The identification of distinct ischemic MRI signatures associated with specific tissue fates may further aid in assessing and monitoring the efficacy of novel pharmaceutical treatments for stroke in a pre-clinical and clinical setting.
Jafari-Khouzani K, Emblem KE, Kalpathy-Cramer J, Bjørnerud A, Vangel MG, Gerstner ER, Schmainda KM, Paynabar K, Wu O, Wen PY, Batchelor T, Rosen B, Stufflebeam SM. Repeatability of Cerebral Perfusion Using Dynamic Susceptibility Contrast MRI in Glioblastoma Patients. Transl Oncol 2015;8(3):137-46.Abstract
OBJECTIVES: This study evaluates the repeatability of brain perfusion using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with a variety of post-processing methods. METHODS: Thirty-two patients with newly diagnosed glioblastoma were recruited. On a 3-T MRI using a dual-echo, gradient-echo spin-echo DSC-MRI protocol, the patients were scanned twice 1 to 5 days apart. Perfusion maps including cerebral blood volume (CBV) and cerebral blood flow (CBF) were generated using two contrast agent leakage correction methods, along with testing normalization to reference tissue, and application of arterial input function (AIF). Repeatability of CBV and CBF within tumor regions and healthy tissues, identified by structural images, was assessed with intra-class correlation coefficients (ICCs) and repeatability coefficients (RCs). Coefficients of variation (CVs) were reported for selected methods. RESULTS: CBV and CBF were highly repeatable within tumor with ICC values up to 0.97. However, both CBV and CBF showed lower ICCs for healthy cortical tissues (up to 0.83), healthy gray matter (up to 0.95), and healthy white matter (WM; up to 0.93). The values of CV ranged from 6% to 10% in tumor and 3% to 11% in healthy tissues. The values of RC relative to the mean value of measurement within healthy WM ranged from 22% to 42% in tumor and 7% to 43% in healthy tissues. These percentages show how much variation in perfusion parameter, relative to that in healthy WM, we expect to observe to consider it statistically significant. We also found that normalization improved repeatability, but AIF deconvolution did not. CONCLUSIONS: DSC-MRI is highly repeatable in high-grade glioma patients.
Wu O, Cloonan L, Mocking SJT, Bouts MJRJ, Copen WA, Cougo-Pinto PT, Fitzpatrick K, Kanakis A, Schaefer PW, Rosand J, Furie KL, Rost NS. Role of Acute Lesion Topography in Initial Ischemic Stroke Severity and Long-Term Functional Outcomes. Stroke 2015;46(9):2438-44.Abstract
BACKGROUND AND PURPOSE: Acute infarct volume, often proposed as a biomarker for evaluating novel interventions for acute ischemic stroke, correlates only moderately with traditional clinical end points, such as the modified Rankin Scale. We hypothesized that the topography of acute stroke lesions on diffusion-weighted magnetic resonance imaging may provide further information with regard to presenting stroke severity and long-term functional outcomes. METHODS: Data from a prospective stroke repository were limited to acute ischemic stroke subjects with magnetic resonance imaging completed within 48 hours from last known well, admission NIH Stroke Scale (NIHSS), and 3-to-6 months modified Rankin Scale scores. Using voxel-based lesion symptom mapping techniques, including age, sex, and diffusion-weighted magnetic resonance imaging lesion volume as covariates, statistical maps were calculated to determine the significance of lesion location for clinical outcome and admission stroke severity. RESULTS: Four hundred ninety subjects were analyzed. Acute stroke lesions in the left hemisphere were associated with more severe NIHSS at admission and poor modified Rankin Scale at 3 to 6 months. Specifically, injury to white matter (corona radiata, internal and external capsules, superior longitudinal fasciculus, and uncinate fasciculus), postcentral gyrus, putamen, and operculum were implicated in poor modified Rankin Scale. More severe NIHSS involved these regions, as well as the amygdala, caudate, pallidum, inferior frontal gyrus, insula, and precentral gyrus. CONCLUSIONS: Acute lesion topography provides important insights into anatomic correlates of admission stroke severity and poststroke outcomes. Future models that account for infarct location in addition to diffusion-weighted magnetic resonance imaging volume may improve stroke outcome prediction and identify patients likely to benefit from aggressive acute intervention and personalized rehabilitation strategies.