Identifying potential predictable indicators for the management of tertiary hospitals.

BACKGROUND: The European University Hospitals Alliance (EUHA) recognises the need to move from the classical approach of measuring key performance indicators (KPIs) to an anticipative approach based on predictable indicators to take decisions (Key Decision Indicators, KDIs). It might help managers to anticipate poor results before they occur to prevent or correct them early. OBJECTIVE: This paper aims to identify potential KDIs and to prioritize those most relevant for high complexity hospitals. METHODS: A narrative review was performed to identify KPIs with the potential to become KDIs. Then, two surveys were conducted with EUHA hospital managers (n = 51) to assess potential KDIs according to their relevance for decision-making (Value) and their availability and effort required to be predicted (Feasibility). Potential KDIs are prioritized for testing as predictable indicators and developing in the short term if they were classified as highly Value and Feasible. RESULTS: The narrative review identified 45 potential KDIs out of 153 indicators and 11 were prioritized. Of nine EUHA hospitals, 25 members from seven answered, prioritizing KDIs related to the emergency department (ED), hospitalisation and surgical processes (n = 8), infrastructure and resources (n = 2) and health outcomes and quality (n = 1). The highest scores in this group were for those related to ED. The results were homogeneous among the different hospitals. CONCLUSIONS: Potential KDIs related to care processes and hospital patient flow was the most prioritized ones to test as being predictable. KDIs represent a new approach to decision-making, whose potential to be predicted could impact the planning and management of hospital resources and, therefore, healthcare quality.

Imperceptible somatosensory stimulation alters sensorimotor background rhythm and connectivity.

Most sensory input to our body is not consciously perceived. Nevertheless, it may reach the cortex and influence our behavior. In this study, we investigated noninvasive neural signatures of unconscious cortical stimulus processing to understand mechanisms, which (1) prevent low-intensity somatosensory stimuli from getting access to conscious experience and which (2) can explain the associated impediment of conscious perception for additional stimuli. Stimulation of digit 2 in humans far below the detection threshold elicited a cortical evoked potential (P1) at 60 ms, but no further somatosensory evoked potential components. No event-related desynchronization was detected; rather, there was a transient synchronization in the alpha frequency range. Using the same stimulation during fMRI, a reduced centrality of contralateral primary somatosensory cortex (SI) was found, which appeared to be mainly driven by reduced functional connectivity to frontoparietal areas. We conclude that after subthreshold stimulation the (excitatory) feedforward sweep of bottom-up processing terminates in SI preventing access to conscious experience. We speculate that this interruption is due to a predominance of inhibitory processing in SI. The increase in alpha activity and the disconnection of SI from frontoparietal areas are likely correlates of an elevated perception threshold and may thus serve as a gating mechanism for the access to conscious experience.

Social work after stroke: identifying demand for support by recording stroke patients' and carers' needs in different phases after stroke.

BACKGROUND: Previous studies examining social work interventions in stroke often lack information on content, methods and timing over different phases of care including acute hospital, rehabilitation and out-patient care. This limits our ability to evaluate the impact of social work in multidisciplinary stroke care. We aimed to quantify social-work-related support in stroke patients and their carers in terms of timing and content, depending on the different phases of stroke care. METHODS: We prospectively collected and evaluated data derived from a specialized "Stroke-Service-Point" (SSP); a "drop in" center and non-medical stroke assistance service, staffed by social workers and available to all stroke patients, their carers and members of the public in the metropolitan region of Berlin, Germany. RESULTS: Enquiries from 257 consenting participants consulting the SSP between March 2010 and April 2012 related to out-patient and in-patient services, therapeutic services, medical questions, medical rehabilitation, self-help groups and questions around obtaining benefits. Frequency of enquiries for different topics depended on whether patients were located in an in-patient or out-patient setting. The majority of contacts involved information provision. While the proportion of male and female patients with stroke was similar, about two thirds of the carers contacting the SSP were female. CONCLUSION: The social-work-related services provided by a specialized center in a German metropolitan area were diverse in terms of topic and timing depending on the phase of stroke care. Targeting the timing of interventions might be important to increase the impact of social work on patient's outcome.

A validation study of the use of near-infrared spectroscopy imaging in primary and secondary motor areas of the human brain.

The electroencephalographically measured Bereitschafts (readiness)-potential in the supplementary motor area (SMA) serves as a signature of the preparation of motor activity. Using a multichannel, noninvasive near-infrared spectroscopy (NIRS) imager, we studied the vascular correlate of the readiness potential. Sixteen healthy subjects performed a self-paced or externally triggered motor task in a single or repetitive pattern, while NIRS simultaneously recorded the task-related responses of deoxygenated hemoglobin (HbR) in the primary motor area (M1) and the SMA. Right-hand movements in the repetitive sequence trial elicited a significantly greater HbR response in both the SMA and the left M1 compared to left-hand movements. During the single sequence condition, the HbR response in the SMA, but not in the M1, was significantly greater for self-paced than for externally cued movements. Nonetheless, an unequivocal temporal delay was not found between the SMA and M1. Near-infrared spectroscopy is a promising, noninvasive bedside tool for the neuromonitoring of epileptic seizures or cortical spreading depolarizations (CSDs) in patients with epilepsy, stroke, or brain trauma because these pathological events are associated with typical spatial and temporal changes in HbR. Propagation is a characteristic feature of these events which importantly supports their identification and characterization in invasive recordings. Unfortunately, the present noninvasive study failed to show a temporal delay during self-paced movements between the SMA and M1 as a vascular correlate of the readiness potential. Although this result does not exclude, in principle, the possibility that scalp-NIRS can detect a temporal delay between different regions during epileptic seizures or CSDs, it strongly suggests that further technological development of NIRS should focus on both improved spatial and temporal resolution. This article is part of a Special Issue entitled Status Epilepticus.

Monochromatic ultra-slow (~0.1 Hz) oscillations in the human electroencephalogram and their relation to hemodynamics.

Previous studies demonstrated the presence of Monochromatic Ultra-Slow Oscillations (MUSO) in human EEG. In the present study we explored the biological origin of MUSO by simultaneous recordings of EEG, Near-Infrared Spectroscopy (NIRS), arterial blood pressure, respiration and Laser Doppler flowmetry. We used a head-up tilt test in order to check whether MUSO might relate to Mayer waves in arterial blood pressure, known to be enhanced by the tilting procedure. MUSO were detected in 8 out of 10 subjects during rest and showed a striking monochromatic spectrum (0.07-0.14 Hz). The spatial topography of MUSO was complex, showing multiple foci variable across subjects. While the head-up tilt test increased the relative power of Mayer waves, it had no effect on MUSO. On the other hand, the relative spectral power of 0.1 Hz oscillations in EEG, NIRS and blood pressure signals were positively correlated across subjects in the tilted condition. Eight subjects showed a coherence between MUSO and NIRS/arterial blood pressure. Moreover, MUSO at different electrode sites demonstrated coherence not reducible to volume conduction, thus indicating that MUSO are unlikely to be generated by one source. We related our experimental findings to known biological phenomena being generated at about 0.1 Hz, i.e.: arterial blood pressure, cerebral and skin vasomotion, respiration and neuronal activity. While no definite conclusion can yet be drawn as to an exact physiological mechanism of MUSO, we suggest that these oscillations might be of a rather extraneuronal origin reflecting cerebral vasomotion.

A wearable multi-channel fNIRS system for brain imaging in freely moving subjects.

Functional near infrared spectroscopy (fNIRS) is a versatile neuroimaging tool with an increasing acceptance in the neuroimaging community. While often lauded for its portability, most of the fNIRS setups employed in neuroscientific research still impose usage in a laboratory environment. We present a wearable, multi-channel fNIRS imaging system for functional brain imaging in unrestrained settings. The system operates without optical fiber bundles, using eight dual wavelength light emitting diodes and eight electro-optical sensors, which can be placed freely on the subject's head for direct illumination and detection. Its performance is tested on N=8 subjects in a motor execution paradigm performed under three different exercising conditions: (i) during outdoor bicycle riding, (ii) while pedaling on a stationary training bicycle, and (iii) sitting still on the training bicycle. Following left hand gripping, we observe a significant decrease in the deoxyhemoglobin concentration over the contralateral motor cortex in all three conditions. A significant task-related ΔHbO2 increase was seen for the non-pedaling condition. Although the gross movements involved in pedaling and steering a bike induced more motion artifacts than carrying out the same task while sitting still, we found no significant differences in the shape or amplitude of the HbR time courses for outdoor or indoor cycling and sitting still. We demonstrate the general feasibility of using wearable multi-channel NIRS during strenuous exercise in natural, unrestrained settings and discuss the origins and effects of data artifacts. We provide quantitative guidelines for taking condition-dependent signal quality into account to allow the comparison of data across various levels of physical exercise. To the best of our knowledge, this is the first demonstration of functional NIRS brain imaging during an outdoor activity in a real life situation in humans.

Impact of selection criteria on recruitment in an interventional stroke trial.

BACKGROUND: Randomized controlled clinical trials are the gold standard for scientific evaluation of clinical diagnostic and treatment concepts. Frequently, recruitment of participants is slower than expected, especially in acute conditions with a short time frame for inclusion. Simple prediction models have been proposed to extrapolate recruitment rates. We hypothesized a significant overestimation of recruitment when ignoring interdependence of selection criteria, leading to an insufficient representation of reality by available models. We proposed that slight modifications to inclusion criteria might augment recruitment without causing selection bias. METHODS: We analyzed recruitment in an acute intervention trial of acute ischemic stroke initiated by our facility. Frequencies of selection criteria were recorded and analyzed individually as well as cumulatively. We then amended the trial protocol by moderate modifications to the selection criteria. The main outcome criterion was the rate of recruited over screened patients, with the goal of increasing recruitment fourfold without adding unacceptable selection bias. A previously presented prediction model was applied to our trial and compared with actual recruitment. Data were compared between screening periods at recruitment prior to and after the implementation of the amendments. RESULTS: The impact of typical as well as novel inclusion criteria such as age limits, imaging-based definition of pathology, time between onset and presentation as well as inability to consent were quantified. Age restriction, definition of index event and late arrival after ictus were identified as the most challenging modifiable selection criteria. Amending those criteria increased recruitment by a factor of 4.1. Inability to consent was a significant exclusion criterion gaining impact with the target population. The selection criteria had a cumulative rather than separate recruitment-limiting impact. A previously presented model did not predict recruitment sufficiently. CONCLUSION: We describe frequencies of selection criteria in a typical cohort of patients suffering from acute cerebrovascular events, and their cumulative impact. These data may help to better understand recruitment limitations and allow designing future trials more effectively. Ability to consent especially is a major contributor to trial exclusion, strongly interfering with the targeted trial population of ischemic stroke. Tentative prescreening phases before site or trial initiation should be considered. No predictive statistical models of recruitment have been established so far.

Somatosensory activation of two fingers can be discriminated with ultrahigh-density diffuse optical tomography.

Topographic non-invasive near infrared spectroscopy (NIRS) has become a well-established tool for functional brain imaging. Applying up to 100 optodes over the head of a subject, allows achieving a spatial resolution in the centimeter range. This resolution is poor compared to other functional imaging tools. However, recently it was shown that diffuse optical tomography (DOT) as an extension of NIRS based on high-density (HD) probe arrays and supplemented by an advanced image reconstruction procedure allows describing activation patterns with a spatial resolution in the millimeter range. Building on these findings, we hypothesize that HD-DOT may render very focal activations accessible which would be missed by the traditionally used sparse arrays. We examined activation patterns in the primary somatosensory cortex, since its somatotopic organization is very fine-grained. We performed a vibrotactile stimulation study of the first and fifth finger in eight human subjects, using a 900-channel continuous-wave DOT imaging system for achieving a higher resolution than conventional topographic NIRS. To compare the results to a well-established high-resolution imaging technique, the same paradigm was investigated in the same subjects by means of functional magnetic resonance imaging (fMRI). In this work, we tested the advantage of ultrahigh-density probe arrays and show that highly focal activations would be missed by classical next-nearest neighbor NIRS approach, but also by DOT, when using a sparse probe array. Distinct activation patterns for both fingers correlated well with the expected neuroanatomy in five of eight subjects. Additionally we show that activation for different fingers is projected to different tissue depths in the DOT image. Comparison to the fMRI data yielded similar activation foci in seven out of ten finger representations in these five subjects when comparing the lateral localization of DOT and fMRI results.

Enhanced performance by a hybrid NIRS-EEG brain computer interface.

Noninvasive Brain Computer Interfaces (BCI) have been promoted to be used for neuroprosthetics. However, reports on applications with electroencephalography (EEG) show a demand for a better accuracy and stability. Here we investigate whether near-infrared spectroscopy (NIRS) can be used to enhance the EEG approach. In our study both methods were applied simultaneously in a real-time Sensory Motor Rhythm (SMR)-based BCI paradigm, involving executed movements as well as motor imagery. We tested how the classification of NIRS data can complement ongoing real-time EEG classification. Our results show that simultaneous measurements of NIRS and EEG can significantly improve the classification accuracy of motor imagery in over 90% of considered subjects and increases performance by 5% on average (p<0:01). However, the long time delay of the hemodynamic response may hinder an overall increase of bit-rates. Furthermore we find that EEG and NIRS complement each other in terms of information content and are thus a viable multimodal imaging technique, suitable for BCI.

Contrast enhanced high-resolution diffuse optical tomography of the human brain using ICG.

Non-invasive diffuse optical tomography (DOT) of the adult brain has recently been shown to improve the spatial resolution for functional brain imaging applications. Here we show that high-resolution (HR) DOT is also advantageous for clinical perfusion imaging using an optical contrast agent. We present the first HR-DOT results with a continuous wave near infrared spectroscopy setup using a dense grid of optical fibers and indocyanine green (ICG) as an exogenic contrast agent. We find an early arrival of the ICG bolus in the intracerebral tissue and a delayed arrival of the bolus in the extracerebral tissue, achieving the separation of both layers. This demonstrates the method's potential for brain perfusion monitoring in neurointensive care patients.

Stimulus-induced and state-dependent sustained gamma activity is tightly coupled to the hemodynamic response in humans.

A prompt behavioral response to a stimulus depends both on the salience of the stimulus as well as the subject's preparedness. Thus, both stimulus properties and cognitive factors, such as attention, may determine the strength of neuronal synchronization in the gamma range. For a comprehensive investigation of stimulus-response processing through noninvasive imaging, it is, however, a crucial issue whether both kinds of gamma modulation elicit a hemodynamic response. Here, we show that, in the human visual cortex, stimulus strength and internal state modulate sustained gamma activity and hemodynamic response in close correspondence. When participants reported velocity changes of gratings varying in contrast, gamma activity (35-70 Hz) increased systematically with contrast. For stimuli of constant contrast, the amplitude of gamma activity before the behaviorally relevant velocity change was inversely correlated to the behavioral response latency. This indicates that gamma activity also reflects an overall attentive state. For both sources of variance, gamma activity was tightly coupled to the hemodynamic response measured through optical topography. Because of the close relationship between high-frequency neuronal activity and the hemodynamic signal, we conclude that both stimulus-induced and state-dependent gamma activity trigger a metabolic demand and are amenable to vascular-based imaging.

Sensitivity of newborn auditory cortex to the temporal structure of sounds.

Understanding the rapidly developing building blocks of speech perception in infancy requires a close look at the auditory prerequisites for speech sound processing. Pioneering studies have demonstrated that hemispheric specializations for language processing are already present in early infancy. However, whether these computational asymmetries can be considered a function of linguistic attributes or a consequence of basic temporal signal properties is under debate. Several studies in adults link hemispheric specialization for certain aspects of speech perception to an asymmetry in cortical tuning and reveal that the auditory cortices are differentially sensitive to spectrotemporal features of speech. Applying concurrent electrophysiological (EEG) and hemodynamic (near-infrared spectroscopy) recording to newborn infants listening to temporally structured nonspeech signals, we provide evidence that newborns process nonlinguistic acoustic stimuli that share critical temporal features with language in a differential manner. The newborn brain preferentially processes temporal modulations especially relevant for phoneme perception. In line with multi-time-resolution conceptions, modulations on the time scale of phonemes elicit strong bilateral cortical responses. Our data furthermore suggest that responses to slow acoustic modulations are lateralized to the right hemisphere. That is, the newborn auditory cortex is sensitive to the temporal structure of the auditory input and shows an emerging tendency for functional asymmetry. Hence, our findings support the hypothesis that development of speech perception is linked to basic capacities in auditory processing. From birth, the brain is tuned to critical temporal properties of linguistic signals to facilitate one of the major needs of humans: to communicate.

Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage.

The term cortical spreading depolarization (CSD) describes a wave of mass neuronal depolarization associated with net influx of cations and water. Clusters of prolonged CSDs were measured time-locked to progressive ischaemic damage in human cortex. CSD induces tone alterations in resistance vessels, causing either transient hyperperfusion (physiological haemodynamic response) in healthy tissue; or hypoperfusion [inverse haemodynamic response = cortical spreading ischaemia (CSI)] in tissue at risk for progressive damage, which has so far only been shown experimentally. Here, we performed a prospective, multicentre study in 13 patients with aneurysmal subarachnoid haemorrhage, using novel subdural opto-electrode technology for simultaneous laser-Doppler flowmetry (LDF) and direct current-electrocorticography, combined with measurements of tissue partial pressure of oxygen (ptiO(2)). Regional cerebral blood flow and electrocorticography were simultaneously recorded in 417 CSDs. Isolated CSDs occurred in 12 patients and were associated with either physiological, absent or inverse haemodynamic responses. Whereas the physiological haemodynamic response caused tissue hyperoxia, the inverse response led to tissue hypoxia. Clusters of prolonged CSDs were measured in five patients in close proximity to structural brain damage as assessed by neuroimaging. Clusters were associated with CSD-induced spreading hypoperfusions, which were significantly longer in duration (up to 144 min) than those of isolated CSDs. Thus, oxygen depletion caused by the inverse haemodynamic response may contribute to the establishment of clusters of prolonged CSDs and lesion progression. Combined electrocorticography and perfusion monitoring also revealed a characteristic vascular signature that might be used for non-invasive detection of CSD. Low-frequency vascular fluctuations (LF-VF) (f < 0.1 Hz), detectable by functional imaging methods, are determined by the brain's resting neuronal activity. CSD provides a depolarization block of the resting activity, recorded electrophysiologically as spreading depression of high-frequency-electrocorticography activity. Accordingly, we observed a spreading suppression of LF-VF, which accompanied spreading depression of high-frequency-electrocorticography activity, independently of whether CSD was associated with a physiological, absent or inverse haemodynamic response. Spreading suppressions of LF-VF thus allow the differentiation of progressive ischaemia and repair phases in a fashion similar to that shown previously for spreading depressions of high-frequency-electrocorticography activity. In conclusion, it is suggested that (i) CSI is a novel human disease mechanism associated with lesion development and a potential target for therapeutic intervention in stroke; and that (ii) prolonged spreading suppressions of LF-VF are a novel 'functional marker' for progressive ischaemia.

Time-resolved near-infrared spectroscopy and imaging of the adult human brain.

Near-infrared spectroscopy (NIRS) of the human brain is aiming at the non-invasive determination of concentration changes of oxy- and deoxyhemoglobin in the cortex. However, it usually relies on the assumption of spatially homogeneous absorption changes. To overcome this limitation we performed instrumental and methodological developments of time-resolved NIRS with the aim to achieve depth resolution. We present our recently developed time-domain near-infrared brain imager based on picosecond diode lasers and time-correlated single photon counting (TCSPC) which can be used at the bedside. To achieve depth localization of absorption changes we analysed statistical moments (integral, mean time of flight and variance) of measured time-of-flight distributions of diffusely reflected photons. In particular, variance has a selective sensitivity to deep absorptions changes and provides a suitable representation of cerebral signals. The separation of cerebral and extracerebral changes of hemoglobin concentrations is demonstrated for a motor stimulation experiment.

Dysferlin-deficient muscular dystrophy: gadofluorine M suitability at MR imaging in a mouse model.

PURPOSE: To compare the usefulness of gadofluorine M with that of Gadomer in assessment of dysferlin-deficient muscular dystrophy at 7.0-T magnetic resonance (MR) imaging. MATERIALS AND METHODS: All experiments were approved by local review boards. SJL/J mice (n = 24) with dysferlin-deficient muscular dystrophy and C57BL/6 control mice (n = 24) were imaged at 12-15 weeks (young) or older than 30 weeks (old) by using dynamic contrast material-enhanced imaging with inversion-prepared steady-state free-precession sequence before, during, and after administration of gadofluorine M at 2 micromol or Gadomer at 4 micromol intravenously. After imaging, regions of interest were determined from the upper extremity and left ventricular chamber; fractional extravascular extracellular volume, v(e), and permeability surface tissue density product, PS rho, were measured by using a two-compartment pharmacokinetic model. The natural history of muscular dystrophy was assessed histologically in 70 mice (seven five-mouse groups each of SJL/J mice and of control mice) at 4-week intervals from 8 to 32 weeks. In addition, three SJL/J mice and three control mice at age 33 weeks were sacrificed, and fluorescence microscopy was performed for visualization of intravenously administered carbocyanine-labeled gadofluorine M in muscle cells. Statistical analysis was performed by using the t test. RESULTS: Gadofluorine M enhancement was significantly greater in skeletal muscle of 30-week-old mice with dysferlin-deficient muscular dystrophy, compared with control mice. Gadofluorine M demonstrated both increased rate of enhancement (PS rho sec(-1) +/- standard error of the mean: 0.004 e(-)(4) +/- 3 vs 0.002 e(-)(4) +/- 3; P < .05) and increased level of enhancement (v(e) +/- standard error of the mean: 0.035 +/- 0.004 vs 0.019 +/- 0.004; P < .05). Gadomer showed no differential enhancement in the two mouse groups. Histologic examination confirmed the presence of labeled gadofluorine M in muscle cells. CONCLUSION: Gadofluorine M-enhanced MR imaging may be of value in monitoring dysferlin-deficient muscular dystrophy disease progression in this animal model and could prove to be a useful tool in following the course of chronic muscle diseases in humans.

In vivo imaging of the inflammatory receptor CD40 after cerebral ischemia using a fluorescent antibody.

BACKGROUND AND PURPOSE: Brain inflammation is a hallmark of stroke, where it has been implicated in tissue damage as well as in repair. Imaging technologies that specifically visualize these processes are highly desirable. In this study, we explored whether the inflammatory receptor CD40 can be noninvasively and specifically visualized in mice after cerebral ischemia using a fluorescent monoclonal antibody, which we labeled with the near-infrared fluorescence dye Cy5.5 (Cy5.5-CD40MAb). METHODS: Wild-type and CD40-deficient mice were subjected to transient middle cerebral artery occlusion. Mice were either intravenously injected with Cy5.5-CD40MAb or control Cy5.5-IgGMAb. Noninvasive and ex vivo near-infrared fluorescence imaging was performed after injection of the compounds. Probe distribution and specificity was further assessed with single-plane illumination microscopy, immunohistochemistry, and confocal microscopy. RESULTS: Significantly higher fluorescence intensities over the stroke-affected hemisphere, compared to the contralateral side, were only detected noninvasively in wild-type mice that received Cy5.5-CD40MAb, but not in CD40-deficient mice injected with Cy5.5-CD40MAb or in wild-type mice that were injected with Cy5.5-IgGMAb. Ex vivo near-infrared fluorescence showed an intense fluorescence within the ischemic territory only in wild-type mice injected with Cy5.5-CD40MAb. In the brains of these mice, single-plane illumination microscopy demonstrated vascular and parenchymal distribution, and confocal microscopy revealed a partial colocalization of parenchymal fluorescence from the injected Cy5.5-CD40MAb with activated microglia and blood-derived cells in the ischemic region. CONCLUSIONS: The study demonstrates that a CD40-targeted fluorescent antibody enables specific noninvasive detection of the inflammatory receptor CD40 after cerebral ischemia using optical techniques.

Fluorescence tomography technique optimized for noninvasive imaging of the mouse brain.

In vivo molecular fluorescence tomography of brain disease mouse models has two very specific demands on the optical setup: the use of pigmented furry mice does not allow for a purely noncontact setup, and a high spatial accuracy is required on the dorsal side of the animal due to the location of the brain. We present an optimized setup and tomographic scheme that meet these criteria through a combined CW reflectance-transmittance fiber illumination approach and a charge-coupled device contactless detection scheme. To consider the anatomy of the mouse head and take short source detector separations into account, the forward problem was evaluated by a Monte Carlo simulation input with a magnetic resonance image of the animal. We present an evaluation of reconstruction performance of the setup under three different condition. (i) Using a simulated dataset, with well-defined optical properties and low noise, the reconstructed position accuracy is below 0.5 mm. (ii) Using experimental data on a cylindrical tissue-simulating phantom with well-defined optical properties, a spatial accuracy of about 1 mm was found. (iii) Finally, on an animal model with a fluorescent inclusion in the brain, the target position was reconstructed with an accuracy of 1.6 mm.

Synchronization between background activity and visually evoked potential is not mirrored by focal hyperoxygenation: implications for the interpretation of vascular brain imaging.

We performed an electroencephalography and optical topography study simultaneously exploring electrophysiological and vascular response magnitude as a function of stimulus frequency. To elicit a response in the visual cortex, subjects were exposed to flicker frequencies varying from 1 to 25 Hz (1 Hz steps, eyes closed). Extending the standard view to compare magnitudes of the evoked neuronal to the evoked vascular response, we additionally investigated modulations of alpha-power, a marker of "background" EEG activity. The results show two discrepancies between the electrophysiological and vascular response: (1) VEP and alpha-power exhibit a discontinuous peak when stimulating at the individual alpha-frequency (IAF) (approximately 10-11 Hz), indicating resonance between background oscillations and evoked response; this is not mirrored by the vascular response. (2) The vascular response, in contrast, steadily increases up to a maximum at 7-8 Hz and slightly decreases with higher frequencies. This continuous frequency dependence is partly reflected by the decrease in alpha-power up to frequencies of 8-9 Hz and a slight increase in alpha-power beyond the IAF resonance. Although indicating an inverse relationship between alpha-power and vascular response, the frequency dependence of the evoked response does not show such a correlation. Thus, electrophysiological resonance between an individual's alpha-frequency and isofrequent stimulation is not mirrored by the vascular response. Also, spontaneous background EEG activity is an important modulator of the vascular response magnitude. We discuss these deviations from a simple one-to-one translation between evoked potential and vascular response amplitude in the light of questions concerning synchronization, attenuation, and induction of background oscillations such as the alpha-rhythm.

Correcting saturation effects of the arterial input function in dynamic susceptibility contrast-enhanced MRI: a Monte Carlo simulation.

To prevent systematic errors in quantitative brain perfusion studies using dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI), a reliable determination of the arterial input function (AIF) is essential. We propose a novel algorithm for correcting distortions of the AIF caused by saturation of the peak amplitude and discuss its relevance for longitudinal studies. The algorithm is based on the assumption that the AIF can be separated into a reliable part at low contrast agent concentrations and an unreliable part at high concentrations. This unreliable part is reconstructed, applying a theoretical framework based on a transport-diffusion theory and using the bolus-shape in the tissue. A validation of the correction scheme is tested by a Monte Carlo simulation. The input of the simulation was a wide range of perfusion, and the main aim was to compare this input to the determined perfusion parameters. Another input of the simulation was an AIF template derived from in vivo measurements. The distortions of this template was modeled via a Rician distribution for image intensities. As for a real DSC-MRI experiment, the simulation returned the AIF and the tracer concentration-dependent signal in the tissue. The novel correction scheme was tested by deriving perfusion parameters from the simulated data for the corrected and the uncorrected case. For this analysis, a common truncated singular value decomposition approach was applied. We find that the saturation effect caused by Rician-distributed noise leads to an overestimation of regional cerebral blood flow and regional cerebral blood volume, as compared to the input parameter. The aberration can be amplified by a decreasing signal-to-noise ratio (SNR) or an increasing tracer concentration. We also find that the overestimation can be successfully eliminated by the proposed saturation-correction scheme. In summary, the correction scheme will allow DSC-MRI to be expanded towards higher tracer concentrations and lower SNR and will help to increase the measurement to measurement reproducibility for longitudinal studies.

Functional imaging with laser speckle contrast analysis: vascular compartment analysis and correlation with laser Doppler flowmetry and somatosensory evoked potentials.

Laser Speckle Contrast Analysis (LASCA), a novel, high-resolution blood flow imaging method, was performed on rat somatosensory cortex during functional activation. In the same animals, cerebral blood flow (CBF) was measured with Laser Doppler Flowmetry. To obtain a quantitative estimate of the underlying neuronal activity, somatosensory evoked potentials were recorded simultaneously with an epidural EEG. Our results show that: 1. CBF changes measured by LASCA or LDF are nonlinearly dependent on the magnitude of electrical neural activity revealed by somatosensory evoked potentials. 2. The magnitude of relative CBF changes measured by LASCA and LDF shows a strong correlation. 3. LASCA imaging localizes the highest relative changes of CBF in microcirculatory areas, with a smaller contribution by larger vessels. This study demonstrates that LASCA is a reliable method that provides 2D-imaging of CBF changes that are comparable to LDF measurements. It further suggests that functional neuroimaging methods based on CBF enhance areas of microcirculation and thus might prove more accurate in localizing neural activity than oxygenation related methods like BOLD-fMRI.