René Knab

Transient Ischemic Attacks Before Ischemic Stroke: Preconditioning the Human Brain? A Multicenter Magnetic Resonance Imaging Study

Background and Purpose— We investigated whether transient ischemic attacks (TIAs) before stroke can induce tolerance by raising the threshold of tissue vulnerability in the human brain. Methods— Sixty-five patients with first-ever ischemic territorial stroke received diffusion- and perfusion-weighted MRI within 12 hours of symptom onset. Epidemiological and clinical data, lesion volumes in T2, apparent diffusion coefficient (ADC) maps and perfusion maps, and cerebral blood flow and cerebral blood volume values were compared between patients with and without a prodromal TIA. Results— Despite similar size and severity of the perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2: 9.1 [interquartile range, 19.7] versus 36.5 [91.2] mL; P =0.014) in patients with a history of TIA (n=16). This was associated with milder clinical deficits. Conclusions— The beneficial effect of TIAs on lesion size in ADC and T2 suggests the existence of endogenous neuroprotection in the human brain.

Subcortical structures involved in pain processing: evidence from single-trial fMRI

&NA; Pain is processed in multiple cortical and subcortical brain areas. Subcortical structures are substantially involved in different processes that are closely linked to pain processing, e.g. motor preparation, autonomic responses, affective components and learning. However, it is unclear to which extent nociceptive information is relayed to and processed in subcortical structures. We used single‐trial functional magnetic resonance imaging (fMRI) to identify subcortical regions displaying hemodynamic responses to painful stimulation. Thulium–YAG (yttrium–aluminum–granate) laser evoked pain stimuli, which have no concomitant tactile component, were applied to either hand of healthy volunteers in a randomized order. This procedure allowed identification of areas displaying differential fMRI responses to right‐ and left‐sided stimuli. Hippocampal complex, amygdala, red nucleus, brainstem and cerebellum were activated in response to painful stimuli. Structures related to the affective processing of pain showed bilateral activation, whereas structures involved in the generation of withdrawal behavior, namely red nucleus, putamen and cerebellum displayed differential (i.e. asymmetric) responses according to the side of stimulation. This suggests that spatial information about the nociceptive stimulus is made available in these structures for the guidance of defensive and withdrawal behavior.

Prediction of Malignant Middle Cerebral Artery Infarction by Early Perfusion- and Diffusion-Weighted Magnetic Resonance Imaging

Background and Purpose— We tested the hypothesis that early diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) allows the prediction of malignant middle cerebral artery (MCA) infarction (MMI). Methods— Thirty-seven patients with acute MCA infarction and proximal vessel occlusion (carotid-T, MCA main stem) were studied by DWI, PWI, and MR angiography within 6 hours of symptom onset. Eleven patients developed MMI, defined by decline of consciousness and radiological signs of space-occupying brain edema. Lesion volumes were retrospectively defined as apparent diffusion coefficient <80% (ADC<80%) and time to peak >+4 seconds (TTP>+4s) compared with the unaffected hemisphere. ADC decrease within the infarct core (ADCcore) and relative ADC within the ADC<80% lesion (rADClesion) were measured. Neurological deficit at admission was assessed with the National Institutes of Health Stroke Scale (NIHSS). Results— Patients with MMI showed larger ADC<80% (median, 157 versus 22 mL; P <0.001) and TTP>+4s (208 versus 125 mL; P <0.001) lesion volumes, smaller TTP/ADC mismatch ratio (1.5 versus 5.5; P <0.001), lower ADCcore values (290 versus 411 mm2/s; P <0.001), lower rADClesion (0.60 versus 0.66; P =0.001), higher frequency of carotid-T occlusion (64% versus 15%; P =0.006), and higher NIHSS score at admission (20 versus 15; P =0.001). Predictors of MMI were as follows for sensitivity and specificity, respectively: ADC<80% >82 mL, 87%, 91%; TTP>+4s >162 mL, 83%, 75%; TTP/ADC mismatch ratio <2.4, 80%, 79%; ADCcore <300 mm2/s, 83%, 85%; rADClesion <0.62, 79%, 74%; and NIHSS score at admission ≥19, 96%, 72%. Conclusions— Quantitative analysis of early DWI and PWI parameters allows the prediction of MMI and can help in the selection of patients for aggressive tissue-protective therapy.

Somatotopic organization of human somatosensory cortices for pain: a single trial fMRI study

The ability to locate pain plays a pivotal role in immediate defense and withdrawal behavior. However, how the brain localizes nociceptive information without additional information from somatotopically organized mechano-receptive pathways is not well understood. To investigate the somatotopic organization of the nociceptive system, we applied Thulium-YAG-laser evoked pain stimuli, which have no concomitant tactile component, to the dorsum of the left hand and foot in randomized order. We used single-trial functional magnetic resonance imaging (fMRI) to assess differential hemodynamic responses to hand and foot stimulation for the group and in a single subject approach. The primary somatosensory cortex (SI) shows a clear somatotopic organization ipsi- and contralaterally to painful stimulation. Furthermore, a differential representation of hand and foot stimulation appeared within the contralateral opercular--insular region of the secondary somatosensory cortex (SII). This result provides evidence that both SI and SII encode spatial information of nociceptive stimuli without additional information from the tactile system and highlights the concept of a redundant representation of basic discriminative stimulus features in human somatosensory cortices, which seems adequate in view of the evolutionary importance of pain perception.

Single trial fMRI reveals significant contralateral bias in responses to laser pain within thalamus and somatosensory cortices.

Pain is processed in multiple brain areas, indicating the complexity of pain perception. The ability to locate pain plays a pivotal role in immediate defense and withdrawal behavior. However, how the brain localizes nociceptive information without additional information from somatotopically organized mechano-receptive pathways is not well understood. We used single-trial functional magnetic resonance imaging (fMRI) to assess hemodynamic responses to right and left painful stimulation. Thulium-YAG-(yttrium-aluminium-granate)-laser-evoked pain stimuli, without concomitant tactile component, were applied to either hand in a randomized order. A contralateral bias of the BOLD response was investigated to determine areas involved in the coding of the side of stimulation, which we observed in primary (SI) and secondary (SII) somatosensory cortex, insula, and the thalamus. This suggests that these structures provide spatial information of selective nociceptive stimuli. More importantly, this contralateral bias of activation allowed functionally segregated activations within the SII complex, the insula, and the thalamus. Only distinct subregions of the SII complex, the posterior insula and the lateral thalamus, but not the remaining SII complex, the anterior insula and the medial thalamus, showed a contralaterally biased representation of painful stimuli. This result supports the hypothesis that sensory-discriminative attributes of painful stimuli, such as those related to body side, are topospecifically represented within the forebrain projections of the nociceptive system and highlights the concept of functional segregation and specialization within these structures.

The influence of extra- and intracranial artery disease on the BOLD signal in FMRI

Functional MRI is based on the vascular response due to neuronal activation. The underlying mechanism of fMRI is the blood oxygenation level-dependent (BOLD) effect-a complex interplay between changes in the cerebral metabolisation rate of oxygen (CMRO2), neurovascular coupling, and the resulting hemodynamic response. An intact neurovascular coupling is essential for the detection of the BOLD signal and it seems likely that a disturbed cerebrovascular reserve capacity (CVRC) alters the BOLD response. We tested the hypothesis that extra- or intracranial artery disease influences the BOLD signal. Twenty-one patients with extra- or intracranial stenosis were studied with BOLD sensitive T2*-weighted MRI. All patients presented with transient or prolonged reversible ischemic symptoms ipsilateral to the artery disease but were asymptomatic at the time point of the MRI study. fMRI was performed employing a simple motor task (fist closure right and left). Additionally, the CVRC was assessed applying carbogen gas during serial T2*-weighted MRI for the calculation of CO(2) reactivity maps of the relative signal change. Signal differences between both hemispheres were compared in individual subjects and with healthy subjects. Patients with disturbed CVRC in the CO(2) reactivity maps showed either a significantly reduced (n = 5) or a negative (n = 1) BOLD signal in the affected compared to the unaffected primary sensorimotor cortex during fist closure. Patients with intact CVRC showed no significant BOLD signal differences between affected and unaffected hemisphere. Extra- or intracranial artery disease influences CVRC and consequently the BOLD signal. This observation is important for the clinical application of fMRI paradigms.

Negative dip in BOLD fMRI is caused by blood flow--oxygen consumption uncoupling in humans.

The sensitivity of MRI for local changes in the deoxyhemoglobin concentration is the basis of the blood oxygen level dependent (BOLD) effect. Time-resolved fMRI studies during visual activation show an early signal intensity (SI) decrease indicating a short lasting uncoupling of oxygen consumption and cerebral blood flow (CBF) before a SI increase due to the overcompensating hemodynamic response occurs. Normal neuronal activity may be preserved despite absent vascular responsiveness. Here we show that a negative BOLD effect occurs during motor activation in an asymptomatic patient with severely disturbed cerebral autoregulation due to extracranial artery disease. This is thought to be due to oxygen consumption in the absence of a hemodynamic response. This rare case of a persisting uncoupling of oxygen metabolism and CBF serves as a model that supports changes of the cerebral blood oxygen saturation as the major contributor of the BOLD effect.

Cerebral Blood Flow Predicts Lesion Growth in Acute Stroke Patients

Background and Purpose— We sought to study the role of MRI-derived cerebral blood flow (CBF) measurements for the prediction of lesion development in acute stroke patients. Methods— Thirty-two patients were treated with tissue plasminogen activator. Diffusion-weighted (DWI) and perfusion-weighted MRI, T2-weighted imaging, and MR angiography were performed before treatment (2.8±0.9 hours after symptom onset) and on follow-up (days 1 and 7). CBF thresholds (12 and 22 mL/100 g per minute) were applied to bolus tracking MRI maps to determine predictive cutoff levels. Results— In 21 patients (group A), the terminal lesion volume (T2-weighted imaging) was larger than the initial DWI lesion volume (89±93 versus 21±38 mL). In 11 patients (group B), the terminal lesion volume was smaller than the initial DWI lesion volume (7±27 versus 15±29 mL). The initial DWI lesion volume did not differ between both groups. The presence of a tissue volume ≥50 mL with a CBF value ≤12 mL/100 g per minute was predictive for lesion enlargement to day 7 in T2-weighted imaging (positive predictive value, 0.80). Conclusions— The presence of a tissue volume ≥50 mL with a CBF value ≤12 mL/100 g per minute predicts further lesion growth in hyperacute stroke patients. MRI-derived CBF values, with all their present limitations, are valuable in early estimation of prognosis of stroke patients.

Apparent Diffusion Coefficient Decreases and Magnetic Resonance Imaging Perfusion Parameters are Associated in Ischemic Tissue of Acute Stroke Patients

Perfusion-and diffusion-weighted magnetic resonance imaging scans are thought to allow the characterization of tissue at risk of infarction. The authors tested the hypothesis that the apparent diffusion coefficient (ADC) decrease should be associated with the severity of the perfusion deficit in ischemic tissue of acute stroke patients. Perfusion-and diffusion-weighted scans were performed in 11 patients with sudden onset of neurologic deficits within the last 6 hours and T2-weighted magnetic resonance imaging scans were obtained after 6 days. Parameter images of the maximum of the contrast agent concentration, time to peak, relative cerebral blood volume, relative cerebral blood flow, and relative mean transit time were computed from the perfusion-weighted data. A threshold function was used to identify tissue volumes with stepwise ADC decreases. An onionlike distribution of successively decreasing ADC values was found, with the lowest ADC in the center of the ischemic region. Correspondingly, tissue perfusion decreased progressively from the periphery toward the ischemic core. This effect was most pronounced in the time-to-peak maps, with a linear association between ADC decrease and time-to-peak increase. Apparent diffusion coefficient values decreased from the periphery toward the ischemic core, and this distribution of ADC values was strongly associated with the severity of the perfusion deficit.

Iomazenil-Single-Photon Emission Computed Tomography Reveals Selective Neuronal Loss in Magnetic Resonance-Defined Mismatch Areas

Background and Purpose— The mismatch of hypoperfused tissue on perfusion imaging and ischemic tissue on diffusion-weighted imaging is used as a surrogate marker for thrombolytic therapy in the extended time window. Mismatch tissue may recover completely, progress toward infarction, or proceed toward incomplete infarction with selective loss of cortical neurons. We used [123I]iomazenil–single-photon emission computed tomography (IMZ-SPECT) to characterize the neuronal integrity of reperfused “tissue at risk of infarction” that appeared morphologically intact on follow-up magnetic resonance imaging (MRI). Methods— Twelve patients with acute stroke with striatocapsular (SC) infarctions were examined with multimodal MRI at days 0, 1, and 7; IMZ-SPECT was performed at days 5 to 15. The PI at day 0, fluid-attenuated inversion recovery (FLAIR) image at day 7, and IMZ-SPECT were coregistered and stereotactically normalized. The mismatch volume of interest (VOI) was defined as the initial PI lesion subtracted by the FLAIR lesion at day 7. An asymmetry ratio (AR) was computed by dividing the mean IMZ uptake of the mismatch VOI by the unaffected mirror VOI. The same AR was computed for signal intensity on FLAIR images at day 7. Three patients with cortical infarctions were included for calibration of the AR. In this group, the VOI consisted of the FLAIR lesion at day 7. Results— All patients with SC infarctions had a large mismatch of initially hypoperfused (112±31 mL; mean±SD) and finally infarcted tissue (19±14 mL). Mean AR of cortical IMZ uptake was 0.85±0.01 in cortical infarctions and 0.95±0.03 in SC infarctions; thereby AR showed a continuous distribution from clearly reduced (0.89) to normal (1.01) in SC infarctions. Mean AR for FLAIR signal intensity was 1.84±0.14 for cortical infarctions and normal (1.01+0.03) for SC infarctions. Conclusions— IMZ-SPECT detected a selective loss of cortical neurons in patients with SC infarctions in transient hypoperfused tissue, which was morphologically intact on MRI.