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

FMRI resting slow fluctuations correlate with the activity of fast cortico-cortical physiological connections

Recording of slow spontaneous fluctuations at rest using functional magnetic resonance imaging (fMRI) allows distinct long-range cortical networks to be identified. The neuronal basis of connectivity as assessed by resting-state fMRI still needs to be fully clarified, considering that these signals are an indirect measure of neuronal activity, reflecting slow local variations in de-oxyhaemoglobin concentration. Here, we combined fMRI with multifocal transcranial magnetic stimulation (TMS), a technique that allows the investigation of the causal neurophysiological interactions occurring in specific cortico-cortical connections. We investigated whether the physiological properties of parieto-frontal circuits mapped with short-latency multifocal TMS at rest may have some relationship with the resting-state fMRI measures of specific resting-state functional networks (RSNs). Results showed that the activity of fast cortico-cortical physiological interactions occurring in the millisecond range correlated selectively with the coupling of fMRI slow oscillations within the same cortical areas that form part of the dorsal attention network, i.e., the attention system believed to be involved in reorientation of attention. We conclude that resting-state fMRI ongoing slow fluctuations likely reflect the interaction of underlying physiological cortico-cortical connections

Drug and disease effects on the human brain studied by functional MRI

Background: With the advent of magnetic resonance imaging (MRI) technology, various functional MRI (fMRI) techniques have become available for non-invasive neuroscientific studies and clinical diagnostics, which have led to a better understanding of the human brain function in normal and diseased subjects. In order to interpret the fMRI results correctly and design optimal research studies it is important to understand both the potentials and limitations associated with each fMRI technique. In this thesis we used two fMRI techniques: arterial spin labeling (ASL) and resting-sate BOLD (blood-oxygen-level dependent) fMRI to study the effects of a CNS-active (central nervous system) drug and neurologic disorder on the human brain function. Purpose: The main research purposes of this thesis are the following: 1) We assess the reproducibility and reliability of rCBF (regional cerebral blood flow) measurements conducted at 3T with pCASL (pseudo continuous ASL) technique; 2) We study the pharmacokinetics of a CNS active drug in normal volunteers by conducting rCBF measurements as a function of time after intake of a single dose of 20 mg d-amphetamine with the pCASL technique; 3) We investigate the possible neurological abnormalities of mild traumatic brain injury (mTBI) patients with chronic fatigue by performing rCBF and resting-sate functional connectivity measurements before, during and after a 20 minute continuous psychomotor vigilance task (PVT). Conclusion: The results from these studies show that the pCASL technique is a relatively robust method for quantitative measurements of rCBF in both normal volunteers and patient subjects. Repeated rCBF measurements with the pCASL method is a non-invasive and sufficiently sensitive approach to assess pharmacokinetic response to CNS active chemicals and should be useful for studying the neurophysiological characteristics in vivo of potential CNS drugs. The results from the mTBI subjects demonstrate that the repeated measurements of rCBF and functional connectivity metrics before, during and after a PVT provide sensitive diagnostic imaging methods to assess neurological abnormality of mTBI patients without apparent neuroanatomical damage. In addition to the clinical diagnostic value, these studies also contribute to important knowledge for the design and analysis of brain functional imaging studies of drugs and neurological diseases

Toward a greater understanding of the brain processes underlying handgrip and handgrip fatigue

Handgrip is a ubiquitous human movement that determines how we interact with our environment. It is involved in almost every aspect of daily life (e.g. opening a door, handling cutlery, using tools) and like all human movement, its application is limited by muscle fatigue. However, the supraspinal mechanisms of handgrip and handgrip fatigue are not fully understood despite the importance of this fundamental movement, numerous publications, and its presence as a longstanding research topic. This thesis investigates the brain mechanisms of handgrip and handgrip fatigue using fMRI. It begins with a review of the literature in Chapter one, which evaluates the theories and evidence for central control of handgrip and muscle fatigue as well as describing the rationale to perform the experiments in this thesis. The methodology and analyses are also reviewed to provide rationale for their use and to facilitate the interpretation of subsequent experimental results. In order to understand the supraspinal mechanisms of handgrip and handgrip fatigue it is logical to first understand the most fundamental grip type (power vs. precision) and pattern (static vs. dynamic) by which handgrip can be performed

Attention in the Brain Under Conditions of Sub-Optimal Alertness: Neurobiological Effects and Individual Differences

Sleep deprivation (SD) is a prevalent problem in modern society, and one that can have serious adverse consequences for health and safety. Critically, even short periods of SD can lead to relatively large decrements in attention, which may in turn cause an individual to neglect important environmental stimuli. In this thesis, I report the results of three experiments designed to investigate the neural bases of attentional declines under conditions of sleep loss and mental fatigue. In two experiments using arterial spin labeled fMRI, a technique that enables the quantification of absolute levels of cerebral blood flow (CBF), it was found that CBF patterns in the resting brain differed significantly based on arousal levels (Study #1) and prior cognitive workload (Study #2). These findings are a departure from prior neuroimaging studies, which have typically taken neural activity during non-task periods as static and inseparable baseline. In a test of sustained attention, performance declines were observed both following SD (Study #1) and when performing the task for an extended period of time while well-rested (Study #2). These decrements were primarily mediated by hypoactivation in a fronto-parietal attentional circuit. Furthermore, resting baseline levels of cerebral blood flow in the thalamus and prefrontal cortex before the start of the task were predictive of interindividual differences in subsequent performance decline (Study #2). In Study #3, an experiment using standard BOLD fMRI, it was found that performance declines in a test of selective attention following SD were accompanied by reduced functional connectivity between top-down control areas and regions of ventral visual cortex, as well as reductions in activation to targets in object-selective areas. Taken together, these results further our understanding of the neural basis of attention under conditions when this system is taxed beyond its normal limits

Mind over chatter: plastic up-regulation of the fMRI alertness network by EEG neurofeedback

EEG neurofeedback (NFB) is a brain-computer interface (BCI) approach used to shape brain oscillations by means of real-time feedback from the electroencephalogram (EEG), which is known to reflect neural activity across cortical networks. Although NFB is being evaluated as a novel tool for treating brain disorders, evidence is scarce on the mechanism of its impact on brain function. In this study with 34 healthy participants, we examined whether, during the performance of an attentional auditory oddball task, the functional connectivity strength of distinct fMRI networks would be plastically altered after a 30-min NFB session of alpha-band reduction (n=17) versus a sham-feedback condition (n=17). Our results reveal that compared to sham, NFB induced a specific increase of functional connectivity within the alertness/salience network (dorsal anterior and mid cingulate), which was detectable 30 minutes after termination of training. Crucially, these effects were significantly correlated with reduced mind-wandering 'on-task' and were coupled to NFB-mediated resting state reductions in the alpha-band (8-12 Hz). No such relationships were evident for the sham condition. Although group default-mode network (DMN) connectivity was not significantly altered following NFB, we observed a positive association between modulations of resting alpha amplitude and precuneal connectivity, both correlating positively with frequency of mind-wandering. Our findings demonstrate a temporally direct, plastic impact of NFB on large-scale brain functional networks, and provide promising neurobehavioral evidence supporting its use as a noninvasive tool to modulate brain function in health and disease

Resisting Sleep Pressure:Impact on Resting State Functional Network Connectivity

In today's 24/7 society, sleep restriction is a common phenomenon which leads to increased levels of sleep pressure in daily life. However, the magnitude and extent of impairment of brain functioning due to increased sleep pressure is still not completely understood. Resting state network (RSN) analyses have become increasingly popular because they allow us to investigate brain activity patterns in the absence of a specific task and to identify changes under different levels of vigilance (e.g. due to increased sleep pressure). RSNs are commonly derived from BOLD fMRI signals but studies progressively also employ cerebral blood flow (CBF) signals. To investigate the impact of sleep pressure on RSNs, we examined RSNs of participants under high (19 h awake) and normal (10 h awake) sleep pressure with three imaging modalities (arterial spin labeling, BOLD, pseudo BOLD) while providing confirmation of vigilance states in most conditions. We demonstrated that CBF and pseudo BOLD signals (measured with arterial spin labeling) are suited to derive independent component analysis based RSNs. The spatial map differences of these RSNs were rather small, suggesting a strong biological substrate underlying these networks. Interestingly, increased sleep pressure, namely longer time awake, specifically changed the functional network connectivity (FNC) between RSNs. In summary, all FNCs of the default mode network with any other network or component showed increasing effects as a function of increased 'time awake'. All other FNCs became more anti-correlated with increased 'time awake'. The sensorimotor networks were the only ones who showed a within network change of FNC, namely decreased connectivity as function of 'time awake'. These specific changes of FNC could reflect both compensatory mechanisms aiming to fight sleep as well as a first reduction of consciousness while becoming drowsy. We think that the specific changes observed in functional network connectivity could imply an impairment of information transfer between the affected RSNs