The Correlation between Astrocytic Calcium and fMRI Signals is Related to the Thalamic Regulation of Cortical States

BOLD fMRI has been wildly used for mapping brain activity, but the cellular contribution of BOLD signals is still controversial. In this study, we investigated the correlation between neuronal/astrocytic calcium and the BOLD signal using simultaneous GCaMP-mediated calcium and BOLD signal recording, in the event-related state and in resting state, in anesthetized and in free-moving rats. To our knowledge, the results provide the first demonstration that evoked and intrinsic astrocytic calcium signals could occur concurrently accompanied by opposite BOLD signals which are associated with vasodilation and vasoconstriction. We show that the intrinsic astrocytic calcium is involved in brain state changes and is related to the activation of central thalamus. First, by simultaneous LFP and fiber optic calcium recording, the results show that the coupling between LFP and calcium indicates that neuronal activity is the basis of the calcium signal in both neurons and astrocytes. Second, we found that evoked neuronal and astrocytic calcium signals are always positively correlated with BOLD responses. However, intrinsic astrocytic calcium signals are accompanied by the activation of the central thalamus followed by a striking negative BOLD signal in cortex, which suggests that central thalamus may be involved in the initiation of the intrinsic astrocytic calcium signal. Third, we confirmed that the intrinsic astrocytic calcium signal is preserved in free moving rats. Moreover, the occurrences of intrinsic astrocytic calcium spikes are coincident with the transition between different sleep stages, which suggests intrinsic astrocytic calcium spikes reflect brain state transitions. These results demonstrate that the correlation between astrocytic calcium and fMRI signals is related to the thalamic regulation of cortical states. On the other hand, by studying the relationship between vessel–specific BOLD signals and spontaneous calcium activity from adjacent neurons, we show that low frequency spontaneous neuronal activity is the cellular mechanism of the BOLD signal during resting state

The (un)conscious mouse as a model for human brain functions: key principles of anesthesia and their impact on translational neuroimaging

In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca(2+) imaging and fMRI of anesthetic effects to findings from human studies, this systematic review proposes general principles to design, apply and monitor anesthetic protocols in a more sophisticated way. The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species

EFFECTS OF NEUROMODULATION ON NEUROVASCULAR COUPLING

The communication between neurons within neural circuits relies on neurotransmitters (glutamate, γ-aminobutyric acid (GABA)) and neuromodulators (acetylcholine, dopamine, serotonin, etc.). However, despite sharing similar molecular elements, neurotransmitters and neuromodulators are distinct classes of molecules and mediate different aspects of neural activity and metabolism. Neurotransmitters on one hand are responsible for synaptic signal transmission (classical transmission) while neuromodulators exert their functions by mediating different postsynaptic events that result in changes to the balance between excitation and inhibition. Neuromodulation, while essential to nervous system function, has been significantly more difficult to study than neurotransmission. This is principally due to the fact that effects elicited by neuromodulators are usually of slow onset, long lasting, and are not simply excitation or inhibition. In contrast to the effects of neurotransmitters, neuromodulators enable neurons to be more flexible in their ability to encode different sorts of information (e.g. sensory information) on a variety of time scales. However, it is important to appreciate that one of the challenges in the study of neuromodulation is to understand the extent to which neuromodulators’ actions are coordinated at all levels of brain function. That is, from the cellular and metabolic level to network and cognitive control. Therefore, understanding the molecules that mediate brain networks interactions is essential to understanding the brain dynamic, and also helps to put the cellular and molecular processes in perspective. Functional magnetic resonance imaging (fMRI) is a technique that allows access to various cellular and metabolic aspects of network communication that are difficult to access when studying one neuron at the time. Its non-invasiveness nature allows the comparison of data and hypotheses of the primate brain to that of the human brain. Hence, understanding the effects of neuromodulation on local microcircuits is needed. Furthermore, given the massive projections of the neuromodulatory diffuse ascending systems, fMRI combined with pharmacological and neurophysiological methods may provide true insight into their organization and dynamics. However, little is known about how to interpret the effects of neuromodulation in fMRI and neurophysiological data, for instance, how to disentangle blood oxygenation level dependent (BOLD) signal changes relating to cognitive changes (presumably neuromodulatory influences) from stimulus-driven or perceptual effects. The purpose of this dissertation is to understand the causal relationship between neural activity and hemodynamic responses under the influence of neuromodulation. To this end we present the results of six studies. In the first study, we aimed to establish a mass-spectrometry-based technique to uncover the distribution of different metabolites, neurotransmitters and neuromodulators in the macaque brain. We simultaneously measured the concentrations of these biomolecules in brain and in blood. In a second study, we developed a multimodal approach consisting of fMRI (BOLD and cerebral blood flow or CBF), electrophysiological recording with a laminar probe and pharmacology to assess the effects of neuromodulation on neurovascular coupling. We developed a pharmacological injection delivery system using pressure-operated pumps to reliably apply drugs either systemically or intracortically in the NMR scanner. In our third study, we systemically injected lactate and pyruvate to explore whether the plasma concentration of either of these metabolites affects the BOLD responses. This is important given that both metabolites are in a metabolic equilibrium; if this equilibrium is disrupted, changes in the NAD and NADH concentrations would elicit changes in the CBF. In a fourth study, we explored the influence of dopaminergic (DAergic) neuromodulation in the BOLD, CBF and neurophysiological activity. Here we found that DAergic neuromodulation dissociated the BOLD responses from the underlying neural activity. Interestingly, the changes in the neural activity were tightly coupled to the effects seen in the CBF responses. In a subsequent study, we explored whether the effects of dopamine (DA) on the electrophysiological responses are cortical layer dependent and whether specific patterns of neural activity can be used to infer the effects of neuromodulation on the neural activity. This is important, given that different types of neural activity provide independent information about the amplitude and dynamics from BOLD responses, and studies have shown that these bands originate from different cortical layers. What this study revealed, is that local field potentials (LFPs) in the midrange frequencies can indeed provide indications about the sustained effects of neuromodulation on cortical sensory processing. Given the results from the previous study, in our sixth study, we aimed at understanding how different cortical layers may process incoming and outgoing information in the different LFP bands. These findings provide evidence that neuromodulation has profound effects on neurovascular coupling. By changing the excitation-inhibition balance of neural circuits, neuromodulators not only mediate the neural activity, but also adjust the metabolic demands. Therefore, understanding how the different types of neuromodulators affect the BOLD response is essential for an effective interpretation of fMRI-data, not only in tasks involving attentional and reward-related processes, but also for future diagnostic use of fMRI, since many psychiatric disorders are the result of alterations in neuromodulatory systems.Die Kommunikation zwischen den Neuronen innerhalb neuronalen Schaltkreise beruht auf Neurotransmitter (Glutamat, γ-Aminobuttersäure (GABA)) und Neuromodulatoren (Acetylcholin, Dopamin, Serotonin, etc.). Neurotransmitter und Neuromodulatoren sind jedoch unterschiedliche Klassen von Molekülen und verschiedenen Aspekte der neuronalen Aktivität und den Stoffwechsel vermitteln. Neurotransmitters sind einerseits verantwortlich für die synaptische Signalübertragung (klassische Übertragung), während ihre Funktionen ausüben, Neuromodulatoren durch verschiedene postsynaptischen Ereignisse zu vermitteln, die in Änderungen an der Balance zwischen Erregung und Hemmung führen. Neuromodulation , während wesentlich Funktion des Nervensystems hat sich als Neurotransmission wesentlich schwieriger gewesen, zu studieren. Dies ist hauptsächlich auf die Tatsache zurückzuführen, die durch Neuromodulatoren sind in der Regel von langsamen Beginn, langlebig, und sind nicht einfach Anregung oder Hemmung ausgelöst beeinflusst. Im Gegensatz zu den Wirkungen von Neurotransmittern, Neuromodulatoren ermöglichen Neuronen flexibler zu sein in ihrer Fähigkeit, verschiedene Arten von Informationen (beispielsweise sensorische Informationen) auf einer Vielzahl von Zeitskalen zu kodieren. Im Gegensatz zu den Wirkungen von Neurotransmittern, Neuromodulatoren ermöglichen Neuronen flexibler zu sein in ihrer Fähigkeit, verschiedene Arten von Informationen (beispielsweise sensorische Informationen) auf einer Vielzahl von Zeitskalen zu kodieren. Im Gegensatz zu den Wirkungen von Neurotransmittern, Neuromodulatoren ermöglichen Neuronen flexibler zu sein in ihrer Fähigkeit, verschiedene Arten von Informationen (beispielsweise sensorische Informationen) auf einer Vielzahl von Zeitskalen zu kodieren. Jedoch ist es wichtig, dass eine der Herausforderungen bei der Untersuchung von Neuromodulations zu schätzen ist, das Ausmaß, in dem Neuromodulatoren Aktionen koordiniert sind auf allen Ebenen der Gehirnfunktion zu verstehen. Das heißt, von der zellulären und metabolischen Ebene zu vernetzen und kognitive Kontrolle. Daher die Moleküle zu verstehen, die Gehirn Netzwerke Interaktionen vermitteln ist wesentlich für das Verständnis des Gehirns dynamisch, und hilft auch, die zellulären und molekularen Prozesse in Perspektive zu setzen. Funktionellen Kernspintomographie (fMRI) ist eine Technik, die Zugang zu verschiedenen zellulären und metabolischen Aspekte der Netzwerk-Kommunikation ermöglicht, die schwer zugänglich sind, wenn zu der Zeit eines Neurons zu studieren. Seine nicht-Invasivität Natur ermöglicht den Vergleich von Daten und Hypothesen des Primatengehirn zu der des menschlichen Gehirns. Somit wurde das Verständnis der Auswirkungen der Neuromodulation auf lokale Mikro benötigt. Darüber hinaus sind die massiven Projektionen der neuromodulatorischen diffuse Aufstiegsanlagen gegeben, kombiniert fMRI mit pharmakologischen und neurophysiologischen Methoden wahren Einblick in ihre Organisation und Dynamik liefern. Allerdings ist nur wenig darüber bekannt, wie die Auswirkungen der Neuromodulations in fMRI und neurophysiologische Daten zu interpretieren, zum Beispiel, wie Blutoxydation pegelabhängig (BOLD) Signaländerungen in Bezug auf kognitive Veränderungen (vermutlich neuromodulatorischen Einflüsse) von Stimulus-driven oder Wahrnehmungseffekte zu entwirren. Der Zweck dieser Arbeit ist es, die kausale Beziehung zwischen neuronaler Aktivität und hämodynamischen Reaktionen unter dem Einfluss der Neuromodulations zu verstehen. Zu diesem Zweck stellen wir die Ergebnisse von sechs Studien. In der ersten Studie wollten wir eine auf Massenspektrometrie basierende Technik einzurichten, um die Verteilung von verschiedenen Metaboliten, Neurotransmittern und Neuromodulatoren in Makakengehirn aufzudeckenWir maßen gleichzeitig die Konzentrationen dieser Biomoleküle im Gehirn und im Blut. In einer zweiten Studie entwickelten wir einen multimodalen Ansatz, bestehend aus fMRI (BOLD und zerebralen Blutflusses oder CBF), elektrophysiologische Aufzeichnung mit einer laminaren Sonde und Pharmakologie, die Auswirkungen der Neuromodulation auf neurovaskulären Kopplung zu beurteilen. Wir entwickelten eine pharmakologische Injektionsverabreichungssystem druckbetriebenen Pumpen mit zuverlässiger Medikamente gelten entweder systemisch oder intrakortikale im NMR-Scanner. In unserer dritten Studie injizierten wir systemisch Laktat und Pyruvat zu untersuchen, ob die Plasmakonzentration von entweder dieser Metaboliten die BOLD-Antworten beeinflusst. Dies ist wichtig, dass beide gegeben Metaboliten in einem Stoffwechselgleichgewicht sind; wenn dieses Gleichgewicht gestört ist, Veränderungen in den NAD und NADH-Konzentrationen würden Veränderungen in der CBF entlocken. In einer vierten Studie untersuchten wir den Einfluss von dopaminergen (DA-erge) -Neuromodulation im BOLD, CBF und neurophysiologische Aktivität. Hier fanden wir, dass DAerge -Neuromodulation die BOLD-Antworten von der zugrunde liegenden neuronalen Aktivität distanzierte. Interessanterweise waren verbunden, um die Veränderungen in der neuronalen Aktivität eng auf die in den CBF Reaktionen gesehen Wirkungen. In einer nachfolgenden Studie untersuchten wir, ob die Wirkungen von Dopamin (DA) auf die elektrophysiologischen Reaktionen sind Rindenschicht abhängig, und ob bestimmte Muster der neuronalen Aktivität verwendet werden kann, die Wirkungen von Neuromodulations auf die neurale Aktivität zu schließen. Dies ist wichtig, da verschiedene Arten von neuralen Aktivität liefern unabhängige Informationen über die Amplitude und die Dynamik von BOLD-Antworten, und Studien haben gezeigt, dass diese Bands aus verschiedenen kortikalen Schichten stammen. Was diese Studie ergab, dass lokale Feldpotentiale (LFP) in den mittleren Frequenzen in der Tat Hinweise über die nachhaltige Wirkung der Neuromodulation auf die kortikale sensorische Verarbeitung zur Verfügung stellen kann. In Anbetracht der Ergebnisse der früheren Studie, in unserer sechsten Studie wollten wir auf das Verständnis, wie die verschiedenen kortikalen Schichten verarbeiten kann ein- und ausgehenden Informationen in den verschiedenen LFP-Bands. Diese Ergebnisse belegen, dass -Neuromodulation profunde Auswirkungen auf die neurovaskulären Kopplung hat. Durch die Veränderung der Erregungs Hemmung Gleichgewicht neuronaler Schaltkreise vermitteln Neuromodulatoren nicht nur die neurale Aktivität, sondern auch die metabolischen Anforderungen anzupassen. Daher verstehen, wie die verschiedenen Arten von Neuromodulatoren beeinflussen die BOLD-Antwort für eine effektive Interpretation von fMRI-Daten notwendig ist, nicht nur in Aufgaben attentional und Belohnung bezogenen Prozessen mit, sondern auch für zukünftige diagnostische Verwendung von fMRI, da viele psychiatrische Störungen sind das Ergebnis von Veränderungen in neuromodulatorischen Systemen.La comunicación de las neuronas en los circuitos neuronales depende de los neurotransmisores (glutamato, acido γ-amino-butírico o GABA) y los neuromoduladores (acetilcolina, dopamina, serotonina, etc.). Sin embargo, tanto neurotransmisores como neuromoduladores son diferentes clases de moléculas y median diferentes aspectos de la actividad neuronal y del metabolismo, a pesar de compartir elementos moleculares muy similares. Los neurotransmisores, por una lado, son responsables de la transmisión sináptica de la información mientras que los neuromoduladores median diferentes eventos pos-sinápticos que resultan en cambios en el balance de la excitación e inhibición. La influencia de la neuromodulación es esencial para la función del sistema nerviosos, sin embargo es más difícil de estudiar que neurotransmisión. Esto se debe a que los efectos de los neuromoduladores suelen ser de un inicio lento, de larga duración, y no reflejan excitación o inhibición. En contraste a los efectos de los neurotransmisores, los neuromoduladores permiten que las neuronas sean más flexibles en su habilidad de codificar diferentes tipos de información (por ejemplo, información sensorial) en varias escalas temporales. Sin embargo, es importante darse cuenta que uno de objetivos primordiales en el estudio de neuromodulación es el de entender el grado en que la acción de los neuromoduladores está coordinada a todos los niveles de la función cerebral. Es decir, desde los aspectos celulares y metabólicos hasta los niveles de redes neuronales y control cognitivo. Por lo tanto, comprender los forma en la que diferentes moléculas median la interacción entre redes neuronal es esencial para el entendimiento de la dinámica cerebral, y también nos ayudara a comprender los procesos celulares y moleculares asociados a la percepción. La resonancia magnética funcional (fMRI, por sus siglas en inglés) es una técnica que permite acceder a varios aspectos celulares y metabólicos de la comunicación entre redes neuronales que suele ser de difícil acceso. Al mismo tiempo y debido que la fMRI es de naturaleza no invasiva, también permite comparar resultados e hipótesis entre humanos y primates. Por lo tanto, entender los efectos de la neuromodulación en la actividad de los circuitos neuronales es de alta relevancia. Dado que las proyecciones anatómicas de los sistemas de neuromoduladores, el uso de fMRI en combinación con farmacología y neurofisiología puede incrementar nuestro conocimiento sobre la estructura y dinámica de los sistemas de neuromoduladores. Sin embargo, poco se sabe sobre cómo interpretar los efectos de neuromodulation usando fMRI y neurofisiología, por ejemplo, como diferenciar los cambios en la señal BOLD que están relacionados a diferentes estados cognitivos (presumiblemente reflejando la influencia de neuromodulation). El propósito de esta disertación es la de comprender la relación causal que existe entre la actividad neural y la respuesta hemodinámica bajo la influencia de neuromodulación. Para tal fin presentamos los resultados de seis estudios que fueron producto de esta disertacion. En el primer estudio, desarrollamos una técnica basada en espectrometría de masa para detectar y medir la concentración de diferente metabolitos, neurotransmisores y neuromoduladores en el cerebro de primates. Dicha cuantificación se desarrollo simultáneamente tanto in sangre y cerebro. En un segundo estudio, utilizamos varias técnicas de fMRI (BOLD y flujo cerebral sanguíneo, CBF por sus siglas en ingles), registros electrofisiológicos con electrodos laminares y farmacología para acceder a los efectos de neuromodulation en el acople neurovascular. Para este fin, desarrollamos un sistema de inyecciones, basada en cambios de presión, para aplicar substancias sistémicamente o intracorticalmente dentro de un escáner de resonancia magnética. En nuestro tercer estudio, comparamos los efectos de lactato y piruvato para explorar como el desequilibrio metabólico de estas dos substancias afecta la respuesta BOLD. Esto es de gran importancia ya que ambas substancias metabólicas usualmente están en equilibrio. Sin embargo, cuando dicho equilibrio es interrumpido, los procesos metabólicos que acontecen en la mitocondria afectan las concentraciones de NAD y NADH causado cambios en el CBF. En un cuarto estudio, exploramos los efectos de las modulación dopaminergica (DAergic) en las señales BOLD, CBF y en la actividad neuronal. Encontramos que la modulación DAergic disocia las respuesta BOLD de la respuesta neuronal. Interesalmente, los cambios que observamos en la actividad de las neuronas estaba altamente acoplados a los efectos que observamos en la señal de CBF. En un estudio subsecuente, exploramos si los efectos de dopamina en la actividad neuronal es diferentes en las distintas capas de la corteza cerebral. Al mismo tiempo y ya que los neuromoduladores afectan la actividad de circuitos neuronales, exploramos si dichos efectos pueden usados como marcadores de la influencia de la neuromodulación . Esto es importante, ya que diferentes tipos de actividad neuronal brinda información sobre la amplitud y dinámica de la repuesta BOLD, y estudies han demostrado que estas bandas se originan de diferentes capas cortical. Este estudio revelo, que los potenciales de capo (LFPs, por sus siglas en ingles) en frecuencias intermedias puede ser indicativos sobre los efectos de neuromodulation en el procesamiento cortical. Dado los resultados en el estudio previo, en un sexto estudio, nos enfocamos a entender que tan diferentes las capas de la corteza procesan información entrante y saliente en diferentes frecuencias de los LFPs. Estos descubrimientos demuestran que los efectos de los neuromoduladores tiene una fuerte influencia en el acople neurovascular. Los neuromoduladores cambian el balance de excitación e inhibición de los circuitos neuronal, pero también median las demandas metabólicas. De esta manera, entender cómo interpretar los efectos de los neuromoduladores en la respuesta BOLD es esencial para una interpretación veraz y efectiva de los datos generados con fMRI. Estos resultados, no solo nos permiten comprender los procesos que están relacionados a la atención o de varios procesos cognitivos, sino que a su vez, nos permite comprender la señal de fMRI para su futuro uso en la medicina diagnostica, ya que muchas enfermedades psiquiátricas están asociadas a trastornos en el sistemas neuromoduladores

Differential Cortical Activation During the Perception of Moving Objects Along Different Trajectories

Detection of 3D object-motion trajectories depends on the integration of two distinct visual cues: translational displacement and looming. Electrophysiological studies have identified distinct neuronal populations, whose activity depends on the precise motion cues present in the stimulus. This distinction, however, has been less clear in humans, and it is confounded by differences in the behavioral task being performed. We analyzed whole-brain fMRI, while subjects performed a common time-to-arrival task for objects moving along three trajectories: moving directly towards the observer (collision course), with trajectories parallel to the line of sight (passage course), and with trajectories perpendicular to the line of sight (gap closure). We found that there was substantial overlap in the pattern of activation associated with each of the three tasks, with differences among conditions limited to the human motion area (hMT+), which showed greater activation extent in the gap closure condition than for either collision or passage courses. These results support a common substrate for temporal judgments of an object’s time-to-arrival, wherein the special cases of object motion directly toward, or perpendicular to, the observer represent two extremes within the broader continuum of 3D passage trajectories relative to the observer

Neural Representations of Visual Motion Processing in the Human Brain Using Laminar Imaging at 9.4 Tesla

During natural behavior, much of the motion signal falling into our eyes is due to our own movements. Therefore, in order to correctly perceive motion in our environment, it is important to parse visual motion signals into those caused by self-motion such as eye- or head-movements and those caused by external motion. Neural mechanisms underlying this task, which are also required to allow for a stable perception of the world during pursuit eye movements, are not fully understood. Both, perceptual stability as well as perception of real-world (i.e. objective) motion are the product of integration between motion signals on the retina and efference copies of eye movements. The central aim of this thesis is to examine whether different levels of cortical depth or distinct columnar structures of visual motion regions are differentially involved in disentangling signals related to self-motion, objective, or object motion. Based on previous studies reporting segregated populations of voxels in high level visual areas such as V3A, V6, and MST responding predominantly to either retinal or extra- retinal (‘real’) motion, we speculated such voxels to reside within laminar or columnar functional units. We used ultra-high field (9.4T) fMRI along with an experimental paradigm that independently manipulated retinal and extra-retinal motion signals (smooth pursuit) while controlling for effects of eye-movements, to investigate whether processing of real world motion in human V5/MT, putative MST (pMST), and V1 is associated to differential laminar signal intensities. We also examined motion integration across cortical depths in human motion areas V3A and V6 that have strong objective motion responses. We found a unique, condition specific laminar profile in human area V6, showing reduced mid-layer responses for retinal motion only, suggestive of an inhibitory retinal contribution to motion integration in mid layers or alternatively an excitatory contribution in deep and superficial layers. We also found evidence indicating that in V5/MT and pMST, processing related to retinal, objective, and pursuit motion are either integrated or colocalized at the scale of our resolution. In contrast, in V1, independent functional processes seem to be driving the response to retinal and objective motion on the one hand, and to pursuit signals on the other. The lack of differential signals across depth in these regions suggests either that a columnar rather than laminar segregation governs these functions in these areas, or that the methods used were unable to detect differential neural laminar processing. Furthermore, the thesis provides a thorough analysis of the relevant technical modalities used for data acquisition and data analysis at ultra-high field in the context of laminar fMRI. Relying on our technical implementations we were able to conduct two high-resolution fMRI experiments that helped us to further investigate the laminar organization of self-induced and externally induced motion cues in human high-level visual areas and to form speculations about the site and the mechanisms of their integration

The confound of hemodynamic response function variability in human resting-state functional MRI studies

Functional magnetic resonance imaging (fMRI) is an indirect measure of neural activity with the hemodynamic response function (HRF) coupling it with unmeasured neural activity. The HRF, modulated by several non-neural factors, is variable across brain regions, individuals and populations. Yet, a majority of human resting-state fMRI connectivity studies continue to assume a non-variable HRF. In this article, with supportive prior evidence, we argue that HRF variability cannot be ignored as it substantially confounds within-subject connectivity estimates and between-subjects connectivity group differences. We also discuss its clinical relevance with connectivity impairments confounded by HRF aberrations in several disorders. We present limited data on HRF differences between women and men, which resulted in a 15.4% median error in functional connectivity estimates in a group-level comparison. We also discuss the implications of HRF variability for fMRI studies in the spinal cord. There is a need for more dialogue within the community on the HRF confound, and we hope that our article is a catalyst in the process

Functional Magnetic Resonance Imaging

"Functional Magnetic Resonance Imaging - Advanced Neuroimaging Applications" is a concise book on applied methods of fMRI used in assessment of cognitive functions in brain and neuropsychological evaluation using motor-sensory activities, language, orthographic disabilities in children. The book will serve the purpose of applied neuropsychological evaluation methods in neuropsychological research projects, as well as relatively experienced psychologists and neuroscientists. Chapters are arranged in the order of basic concepts of fMRI and physiological basis of fMRI after event-related stimulus in first two chapters followed by new concepts of fMRI applied in constraint-induced movement therapy; reliability analysis; refractory SMA epilepsy; consciousness states; rule-guided behavioral analysis; orthographic frequency neighbor analysis for phonological activation; and quantitative multimodal spectroscopic fMRI to evaluate different neuropsychological states