A novel method of combining blood oxygenation and blood flow sensitive magnetic resonance imaging techniques to measure the cerebral blood flow and oxygen metabolism responses to an unknown neural stimulus.

Simultaneous implementation of magnetic resonance imaging methods for Arterial Spin Labeling (ASL) and Blood Oxygenation Level Dependent (BOLD) imaging makes it possible to quantitatively measure the changes in cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO(2)) that occur in response to neural stimuli. To date, however, the range of neural stimuli amenable to quantitative analysis is limited to those that may be presented in a simple block or event related design such that measurements may be repeated and averaged to improve precision. Here we examined the feasibility of using the relationship between cerebral blood flow and the BOLD signal to improve dynamic estimates of blood flow fluctuations as well as to estimate metabolic-hemodynamic coupling under conditions where a stimulus pattern is unknown. We found that by combining the information contained in simultaneously acquired BOLD and ASL signals through a method we term BOLD Constrained Perfusion (BCP) estimation, we could significantly improve the precision of our estimates of the hemodynamic response to a visual stimulus and, under the conditions of a calibrated BOLD experiment, accurately determine the ratio of the oxygen metabolic response to the hemodynamic response. Importantly we were able to accomplish this without utilizing a priori knowledge of the temporal nature of the neural stimulus, suggesting that BOLD Constrained Perfusion estimation may make it feasible to quantitatively study the cerebral metabolic and hemodynamic responses to more natural stimuli that cannot be easily repeated or averaged

Caffeine-Induced Global Reductions in Resting-State BOLD Connectivity Reflect Widespread Decreases in MEG Connectivity.

In resting-state functional magnetic resonance imaging (fMRI), the temporal correlation between spontaneous fluctuations of the blood oxygenation level dependent (BOLD) signal from different brain regions is used to assess functional connectivity. However, because the BOLD signal is an indirect measure of neuronal activity, its complex hemodynamic nature can complicate the interpretation of differences in connectivity that are observed across conditions or subjects. For example, prior studies have shown that caffeine leads to widespread reductions in BOLD connectivity but were not able to determine if neural or vascular factors were primarily responsible for the observed decrease. In this study, we used source-localized magnetoencephalography (MEG) in conjunction with fMRI to further examine the origins of the caffeine-induced changes in BOLD connectivity. We observed widespread and significant (p < 0.01) reductions in both MEG and fMRI connectivity measures, suggesting that decreases in the connectivity of resting-state neuro-electric power fluctuations were primarily responsible for the observed BOLD connectivity changes. The MEG connectivity decreases were most pronounced in the beta band. By demonstrating the similarity in MEG and fMRI based connectivity changes, these results provide evidence for the neural basis of resting-state fMRI networks and further support the potential of MEG as a tool to characterize resting-state connectivity

Pathophysiological Interference with Neurovascular Coupling – When Imaging Based on Hemoglobin Might Go Blind

Assessing neuronal activity by non-invasive functional brain imaging techniques which are based on the hemodynamic response depends totally on the physiological cascade of metabolism and blood flow. At present, functional brain imaging with near infrared spectroscopy (NIRS) or BOLD-fMRI is widely used in cognitive neuroscience in healthy subjects where neurovascular coupling and cerebrovascular reactivity can be assumed to be intact. Local activation studies as well as studies investigating functional connectivity between brain regions of the resting brain provide a rapidly increasing body of knowledge on brain function in humans and animals. Furthermore, functional NIRS and MRI techniques are increasingly being used in patients with severe brain diseases and this use might gain more and more importance for establishing their use in the clinical routine. However, more and more experimental evidence shows that changes in baseline physiological parameters, pharmacological interventions, or disease-related vascular changes may significantly alter the normal response of blood flow and blood oxygenation and thus may lead to misinterpretation of neuronal activity. In this article we present examples of recent experimental findings on pathophysiological changes of neurovascular coupling parameters in animals and discuss their potential implications for functional imaging based on hemodynamic signals such as fNIRS or BOLD-fMRI. To enable correct interpretation of neuronal activity by vascular signals, future research needs to deepen our understanding of the basic mechanisms of neurovascular coupling and the specific characteristics of disturbed neurovascular coupling in the diseased brain

The effect of caffeine on working memory load-­related brain activation in middle-­aged males

Klaassen, E. B., De Groot, R. H. M., Evers, E. A. T., Snel, J., Veerman, E. C. I., Ligtenberg, A. J. M., Jolles, J., & Veltman, D. J. (2013). The effect of caffeine on working memory load-related brain activation in middle-aged male. Neuropharmacology, 64, 160-167. doi:10.1016/j.neuropharm.2012.06.026Caffeine is commonly consumed in an effort to enhance cognitive performance. However, little is known about the usefulness of caffeine with regard to memory enhancement, with previous studies showing inconsistent effects on memory performance. We aimed to determine the effect of caffeine on working memory (WM) load-related activation during encoding, maintenance and retrieval phases of a WM maintenance task using functional magnetic resonance imaging (fMRI). 20 healthy, male, habitual caffeine consumers aged 40 to 61 years were administered 100 mg of caffeine in a double-blind placebo-controlled crossover design. Participants were scanned in a non-withdrawn state following a workday during which caffeinated products were consumed according to individual normal use (range = 145 – 595 mg). Acute caffeine administration was associated with increased load-related activation compared to placebo in the left and right dorsolateral prefrontal cortex during WM encoding, but decreased load-related activation in the left thalamus during WM maintenance. These findings are indicative of an effect of caffeine on the fronto-parietal network involved in the top-down cognitive control of WM processes during encoding and an effect on the prefrontal cortico-thalamic loop involved in the interaction between arousal and the top-down control of attention during maintenance. Therefore, the effects of caffeine on WM may be attributed to both a direct effect of caffeine on WM processes, as well as an indirect effect on WM via arousal modulation. Behavioral and fMRI results were more consistent with a detrimental effect of caffeine on WM at higher levels of WM load, than caffeine-related WM enhancement

Functional imaging in neuroenhancement

Increasingly demanding tasks, competition for competence and time pressure have lead to attempts of neuroenhancement (NE) among students and employees. NE is designed to increase cognitive abilities by modulating brain processes through the use of pharmaceutics. Substances such as methylphenidate (i.e. Ritalin®), modafinil (i.e. Vigil®) and caffeine are common candidates for enhancing cognitive abilities such as executive functions, inhibition control and memory (Wood et al., 2014). Until today, there has not been a study investigating memory enhancement in functional magnetic resonance imaging (fMRI). Using fMRI, 48 healthy participants were tested for drug effects in a single-dose, double-blind and randomized study using a declarative memory task. During memory recall, methylphenidate dependent deactivations were found in the fronto-parietal and temporal regions whereas no BOLD alterations were seen during encoding. On the behavioral level, methylphenidate enhanced subject’s judgement confidence and performance during late recall. During encoding, caffeine led to deactivations in the precentral gyrus whereas modafinil did not show any BOLD signal alterations at all. To get an overview over the existing neuroimaging literature, all published studies on the effects of the aforementioned drug agents were reviewed in addition. In line with this study, previous publications emphasized that methylphenidate seems to alter task relevant brain areas. Our main finding of task-related deactivations may point to the reduction of task-functioning distractions. Thereby, we conclude a drug-dependent increase of efficiency in data processing.Zunehmende Arbeitsbelastung, erhöhter Zeitdruck und größere Verantwortung haben dazu geführt, dass für Studenten und Arbeitnehmer das Phänomen Neuroenhancement (NE) eine zunehmende Relevanz erlangt hat. Darunter wird die Steigerung der kognitiven Leistung durch pharmazeutischen Eingriff auf zentralnervöse Prozesse verstanden. Substanzen wie z.B. Methylphenidat (Ritalin®), Modafinil (Vigil®) und Koffein gelten als aussichtsreiche Kandidaten zur Leistungssteigerung, die möglicherweise Einfluss auf kognitive Prozesse, wie z.B. Exekutive Funktionen, Inhibitionskontrolle und Gedächtnis ausüben können (Wood et al., 2014). Keine bisher publizierte Studie hat den Fokus auf neuronale Korrelate der deklarativen Gedächtnissteigerung gelegt. Aus dem Grund sind zusätzlich alle bisher veröffentlichten bildgebenden Studien zu Methylphenidat, Modafinil und Koffein zu einer strukturierten Übersicht zusammengefasst worden. Mittels funktionaler Magnetresonanztomographie (fMRT) wurden 48 gesunde Probanden, doppelt verblindet und randomisiert auf Steigerung der deklarativen Gedächtnisleistung getestet. Obwohl die Wirksamkeit der drei Substanzen ausführlich für klinische Patientenpopulationen untersucht wurde, gibt es kaum Wissen über die möglichen behavioralen und neuronalen Auswirkungen auf gesunde, erwachsene Menschen. Entgegen der Erwartung, dass die getesteten Substanzen klassische Gedächtnis assoziierte Regionen aktivieren, wurden unterschiedliche substanzspezifische Effekte gefunden. Wahrend des Abrufs von Gedächtnisinhalten deaktivierte Methylphenidat fronto-parietale und temporale Regionen. Dagegen führte die Applikation von Koffein zu einer verringerten BOLD Antwort im Gyrus Präcentralis während der Lernphase. Modafinil führte zu keiner Veränderung im Vergleich zu Placebo. Auf Verhaltensebene förderte Methylphenidat den späten Abruf von Gedächtnisinhalten, wohingegen die beiden anderen Substanzen keine Effekte hinsichtlich der Lernleistung vorwiesen. Vor dem Hintergrund bisheriger bildgebender Studien zeigt die vorliegende Arbeit, dass Neuroenhancement neben der Aktivierung leistungsrelevanter Gehirnregionen auch durch Reduzierung von störenden Einwirkungen funktionieren kann und damit womöglich die Effektivität der Informationsverarbeitung erhöht

Multiparametric measurement of cerebral physiology using calibrated fMRI

The ultimate goal of calibrated fMRI is the quantitative imaging of oxygen metabolism (CMRO2), and this has been the focus of numerous methods and approaches. However, one underappreciated aspect of this quest is that in the drive to measure CMRO2, many other physiological parameters of interest are often acquired along the way. This can significantly increase the value of the dataset, providing greater information that is clinically relevant, or detail that can disambiguate the cause of signal variations. This can also be somewhat of a double-edged sword: calibrated fMRI experiments combine multiple parameters into a physiological model that requires multiple steps, thereby providing more opportunity for error propagation and increasing the noise and error of the final derived values. As with all measurements, there is a trade-off between imaging time, spatial resolution, coverage, and accuracy. In this review, we provide a brief overview of the benefits and pitfalls of extracting multiparametric measurements of cerebral physiology through calibrated fMRI experiments

Pitfalls in fMRI

Several different techniques allow a functional assessment of neuronal activations by magnetic resonance imaging (fMRI). The by far most influential fMRI technique is based on a local T2*-sensitive hemodynamic response to neuronal activation, also known as the blood oxygenation level dependent or BOLD effect. Consequently, the term ‘fMRI' is often used synonymously with BOLD imaging. Because interpretations of fMRI brain activation maps often appear intuitive and compelling, the reader might be tempted not to critically question the fundamental processes and assumptions. We review some essential processes and assumptions of BOLD fMRI and discuss related confounds and pitfalls in fMRI - from the underlying physiological effect, to data acquisition, data analysis and the interpretation of the results including clinical fMRI. A background framework is provided for the systematic and critical interpretation of fMRI result

Feasibility of using Arterial Spin Labeling for Detecting Longitudinal Changes in Cerebral Blood Flow

The ability of the perfusion MRI technique, arterial spin labeling (ASL), to quantify cerebral blood flow (CBF) makes it attractive for longitudinal studies of changes in brain function, such as those related to chronic pain. However, ASL\u27s poor spatial resolution makes image alignment between sessions difficult, leading to increased variance and greater Type-I errors. In addition, variability due to differences in basal blood flow between sessions and confounding effects such as the arterial transit time (ATT) have the potential to reduce reproducibility over time. The focus of this thesis is to investigate the ability of ASL to detect long-term changes in regional CBF within an individual on a voxel-wise level. It is hypothesized that ASL has the sensitivity to detect activation-induced CBF changes over periods as long as a month if the sources of variance that degrade between-session comparisons are minimized. To test this hypothesis rest and activation (motor task) CBF images were acquired from healthy subjects on three separate imaging sessions. Registration errors were minimized by using individual head molds to replicate the head position in successive sessions. Variations in resting CBF were controlled for by performing the imaging during the same time of day, and subjects were asked to refrain from using common substances, such as caffeine, that are known to affect CBF. Finally, ATT maps were generated on each session to investigate its stability. From these data sets, the within- and between-session variability in CBF was determined and motor-related activation maps were generated from rest and activation data acquired on from the same session and from sessions separated by a week and a month. The results demonstrated excellent reliability (intraclass correlation coefficients greater than 0.75) both within- (0.89 ± 0.2) and between-session (0.84 ± 0.15), and high reproducibility (within subject coefficient of variation, wsCV, greater than 20%) within- (wsCV = 4.7 ± 4.5%) and between-session (wsCV = 5.7 ± 4.4%). Between-session reproducibility of the ATT was high (wsCV = 5.0 ± 2.7%), suggesting that the confounding effect of ATT over a month was minimal. The similarity in within- and between-session variability and their activation maps indicated that registration errors between sessions were minimal. Measures of precision of activation demonstrated that less than ~20% of between-session activation were false positives. These results demonstrate the feasibility of conducting voxel-wise analysis of CBF images acquired on different days and highlight the potential of this technique for longitudinal studies