Background and Purpose— Remote ischemic preconditioning is neuroprotective in models of acute cerebral ischemia. We tested the effect of prehospital rPerC as an adjunct to treatment with intravenous alteplase in patients with acute ischemic stroke. Methods— Open-label blinded outcome proof-of-concept study of prehospital, paramedic-administered rPerC at a 1:1 ratio in consecutive patients with suspected acute stroke. After neurological examination and MRI, patients with verified stroke receiving alteplase treatment were included and received MRI at 24 hours and 1 month and clinical re-examination after 3 months. The primary end point was penumbral salvage, defined as the volume of the perfusion–diffusion mismatch not progressing to infarction after 1 month. Results— Four hundred forty-three patients were randomized after provisional consent, 247 received rPerC and 196 received standard treatment. Patients with a nonstroke diagnosis (n=105) were excluded from further examinations. The remaining patients had transient ischemic attack (n=58), acute ischemic stroke (n=240), or hemorrhagic stroke (n=37). Transient ischemic attack was more frequent ( P =0.006), and National Institutes of Health Stroke Scale score on admission was lower ( P =0.016) in the intervention group compared with controls. Penumbral salvage, final infarct size at 1 month, infarct growth between baseline and 1 month, and clinical outcome after 3 months did not differ among groups. After adjustment for baseline perfusion and diffusion lesion severity, voxelwise analysis showed that rPerC reduced tissue risk of infarction ( P =0.0003). Conclusions— Although the overall results were neutral, a tissue survival analysis suggests that prehospital rPerC may have immediate neuroprotective effects. Future clinical trials should take such immediate effects, and their duration, into account. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00975962.

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

There is considerable intersubject variability in early neurological course after anterior circulation stroke, yet the pathophysiology underlying this variability is not fully understood. Here, we hypothesize that, although not predicted by current pathophysiological models, infarction of 'non-core-non-penumbral' (i.e. clinically silent) brain tissue may nevertheless occur, and negatively influence clinical course over and above the established positive impact of penumbral salvage. In order to test this hypothesis, non-core-non-penumbral tissue was identified in two independent prospectively recruited cohorts, using computed tomography perfusion, and magnetic resonance perfusion- and diffusion-weighted imaging, respectively. Follow-up structural magnetic resonance imaging was obtained about 1 month later in all patients to map the final infarct. The volumes of both the acutely silent but eventually infarcted tissue, and the eventually non-infarcted penumbra, were determined by performing voxel-wise analysis of the acute and follow-up image sets, using previously validated perfusion thresholds. Early neurological course was expressed as change in National Institutes of Health Stroke Scale scores between the acute and 1-month assessments, relative to the acute score. The relationship between the acutely silent but eventually infarcted tissue volume and early neurological course was tested using a multivariate regression model that included the volume of non-infarcted penumbra. Thirty-four and 58 patients were recruited in the computed tomography perfusion and magnetic resonance perfusion cohorts, respectively (mean onset-to-imaging time: 136 and 156 min; 27 and 42 patients received intravenous thrombolysis, respectively). Infarction of acutely silent tissue was identified in most patients in both cohorts. Although its volume (median 0.2 and 2 ml, respectively) was much smaller than that of salvaged penumbra (59.3 and 93 ml, respectively), it was substantial in ∼10% of patients. As expected, salvaged penumbra strongly positively influenced early neurological course. Even after correcting for the latter effect in the multivariate model, infarction of acutely silent tissue independently negatively influenced early neurological course in both cohorts (P=0.018 and 0.031, respectively). This is the first systematic study to document infarction of acutely silent tissue after anterior circulation stroke, and to show that it affects a sizeable fraction of patients and has the predicted negative impact on clinical course. These findings were replicated in two independent cohorts, regardless of the perfusion imaging modality used. Preventing infarction of the tissue not initially at risk should have direct clinical benefit.

Absolute pitch (AP) is the ability to identify or produce pitches of musical tones without an external reference. Active AP (i.e., pitch production or pitch adjustment) and passive AP (i.e., pitch identification) are considered to not necessarily coincide, although no study has properly compared these abilities. Using a novel computerized pitch adjustment test, we investigated active AP ability in musicians with and without AP (ages 18-43). We found a significant correlation between active and passive AP indicating that AP possessors (APs) identify and produce pitch equally well. Furthermore, we found that APs generally undershoot when adjusting musical pitch, a tendency that decreases when musical activity increases. Finally, APs are less accurate when adjusting the pitch to black key targets than to white key targets. Hence, AP ability may be partly practice-dependent and we speculate that APs may benefit from frequent contact with fixed standard chroma to keep in tune.

Background and Purpose-There is ample evidence that in anterior circulation stroke, the diffusion-weighted imaging (DWI) lesion may escape infarction and thus is not a reliable infarct predictor. In this study, we assessed the predictive value of the mean transit time (MTT) for final infarction within the DWI lesion, first in patients scanned back-to-back with 15 O-positron emission tomography and MR (DWI and perfusion-weighted imaging; "Cambridge sample") within 7 to 21 hours of clinical onset, then in a large sample of patients with anterior circulation stroke receiving DWI and perfusion-weighted imaging within 12 hours (85% within 6 hours; "I-KNOW sample"). Methods-Both samples underwent structural MRI at approximately 1 month to map final infarcts. For both imaging modalities, MTT was calculated as cerebral blood volume/cerebral blood flow. After image coregistration and matrix resampling, the MTT values between voxels of interest that later infarcted or not were compared separately within and outside DWI lesions (DWIϩ and DWIϪ, respectively) both within and across patients. In the I-KNOW sample, receiver operating characteristic curves were calculated for these voxel of interest populations and areas under the curve and optimal thresholds calculated. Results-In the Cambridge data set (nϭ4), there was good concordance between predictive values of MTT positron emission tomography and MTT perfusion-weighted imaging for both DWI؉ and DWIϪ voxels of interest indicating adequate reliability of MTT perfusion-weighted imaging for this purpose. In the I-KNOW data set (Nϭ42), the MTT significantly added to the DWI lesion to predict infarction in both DWIϪ and DWI؉ voxels of interest with areas under the curve approximately 0.78 and 0.64 (both PϽ0.001) and optimal thresholds approximately 8 seconds and 11 seconds, respectively. Conclusions-Despite the relatively small samples, this study suggests that adding MTT perfusion-weighted imaging may improve infarct prediction not only as already known outside, but also within, DWI lesions. (Stroke. 2011;42:1602-1607.)