Blood Oxygen Level-dependent Fluctuations Research Articles

Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient

Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level-dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally defined neuroanatomical networks. However, the functional significance of these spontaneous BOLD fluctuations remains poorly understood. By means of 3 T functional MRI, we demonstrate absent cortico-thalamic BOLD functional connectivity (i.e. between posterior cingulate/precuneal cortex and medial thalamus), but preserved cortico-cortical connectivity within the default network in a case of vegetative state (VS) studied 2.5 years following cardio-respiratory arrest, as documented by extensive behavioral and paraclinical assessments. In the VS patient, as in age-matched controls, anticorrelations could also be observed between posterior cingulate/precuneus and a previously identified task-positive cortical network. Both correlations and anticorrelations were significantly reduced in VS as compared to controls. A similar approach in a brain dead patient did not show any such long-distance functional connectivity. We conclude that some slow coherent BOLD fluctuations previously identified in healthy awake human brain can be found in alive but unaware patients, and are thus unlikely to be uniquely due to ongoing modifications of conscious thoughts. Future studies are needed to give a full characterization of default network connectivity in the VS patients population.

The Global Signal and Observed Anticorrelated Resting State Brain Networks

Resting state studies of spontaneous fluctuations in the functional MRI (fMRI) blood oxygen level dependent (BOLD) signal have shown great promise in mapping the brain's intrinsic, large-scale functional architecture. An important data preprocessing step used to enhance the quality of these observations has been removal of spontaneous BOLD fluctuations common to the whole brain (the so-called global signal). One reproducible consequence of global signal removal has been the finding that spontaneous BOLD fluctuations in the default mode network and an extended dorsal attention system are consistently anticorrelated, a relationship that these two systems exhibit during task performance. The dependence of these resting-state anticorrelations on global signal removal has raised important questions regarding the nature of the global signal, the validity of global signal removal, and the appropriate interpretation of observed anticorrelated brain networks. In this study, we investigate several properties of the global signal and find that it is, indeed, global, not residing preferentially in systems exhibiting anticorrelations. We detail the influence of global signal removal on resting state correlation maps both mathematically and empirically, showing an enhancement in detection of system-specific correlations and improvement in the correspondence between resting-state correlations and anatomy. Finally, we show that several characteristics of anticorrelated networks including their spatial distribution, cross-subject consistency, presence with modified whole brain masks, and existence before global regression are not attributable to global signal removal and therefore suggest a biological basis.

Caffeine reduces resting-state BOLD functional connectivity in the motor cortex

In resting-state functional magnetic resonance imaging (fMRI), correlations between spontaneous low-frequency fluctuations in the blood oxygenation level dependent (BOLD) signal are used to assess functional connectivity between different brain regions. Changes in resting-state BOLD connectivity measures are typically interpreted as changes in coherent neural activity across spatially distinct brain regions. However, this interpretation can be complicated by the complex dependence of the BOLD signal on both neural and vascular factors. For example, prior studies have shown that vasoactive agents that alter baseline cerebral blood flow, such as caffeine and carbon dioxide, can significantly alter the amplitude and dynamics of the task-related BOLD response. In this study, we examined the effect of caffeine (200 mg dose) on resting-state BOLD connectivity in the motor cortex across a sample of healthy young subjects ( N = 9). We found that caffeine significantly ( p < 0.05) reduced measures of resting-state BOLD connectivity in the motor cortex. Baseline cerebral blood flow and spectral energy in the low-frequency BOLD fluctuations were also significantly decreased by caffeine. These results suggest that caffeine usage should be carefully considered in the design and interpretation of resting-state BOLD fMRI studies.

Resting-state functional connectivity in animal models: modulations by exsanguination.

We studied the spatiotemporal characteristics of the resting state low frequency fluctuations in functional MRI (fMRI), blood oxygenation level dependent (BOLD) signal in isoflurane-anesthetized rats. fMRI-BOLD measurements at 9.4 Telsa were made during normal and exsanguinated condition previously known to alter cerebral blood flow (CBF) fluctuations in anesthetized rats. fMRI signal time series were low-pass filtered and studied by spectral analysis. During normal conditions, baseline mean arterial pressure (MAP) was 110 +/- 10 mm Hg and low-frequency fluctuations in BOLD signal were observed in the frequency range of 0.01 - 0.125 Hz. Following blood withdrawal (exsanguination), MAP decreased to 68 +/- 7 mm Hg, resulting in an increase in the amplitude of the low-frequency fluctuations in BOLD signal time series and an increase in power at several frequencies between 0.01 and 0.125 Hz. Spatially, the BOLD fluctuations were confined to the cortex and thalamus spanning both hemispheres with sparse presence in the caudate putamen and hippocampus during both normal and exsanguinated states. Spatial distribution of the low frequency fluctuations in BOLD signal, from cross correlation analysis, indicates substantial inter-hemispheric synchrony similar to that observed in the conscious human brain. The behavior of the resting state BOLD signal fluctuations similar to CBF fluctuations during exsanguination indicates a myogenic dependence. Also, a high inter-hemispheric synchrony combined with different phase characteristics of the low frequency BOLD fluctuations particularly in the hippocampus relative to the cortex emphasizes distinct functional networks.

Cluster analysis of resting-state fMRI time series

Functional MRI (fMRI) has become one of the leading methods for brain mapping in neuroscience. Recent advances in fMRI analysis were used to define the default state of brain activity, functional connectivity and basal activity. Basal activity measured with fMRI raised tremendous interest among neuroscientists since synchronized brain activity pattern could be retrieved while the subject rests (resting state fMRI). During recent years, a few signal processing schemes have been suggested to analyze the resting state blood oxygenation level dependent (BOLD) signal from simple correlations to spectral decomposition. In most of these analysis schemes, the question asked was which brain areas “behave” in the time domain similarly to a pre-specified ROI. In this work we applied short time frequency analysis and clustering to study the spatial signal characteristics of resting state fMRI time series. Such analysis revealed that clusters of similar BOLD fluctuations are found in the cortex but also in the white matter and sub-cortical gray matter regions (thalamus). We found high similarities between the BOLD clusters and the neuro-anatomical appearance of brain regions. Additional analysis of the BOLD time series revealed a strong correlation between head movements and clustering quality. Experiments performed with T1-weighted time series also provided similar quality of clustering. These observations led us to the conclusion that non-functional contributions to the BOLD time series can also account for symmetric appearance of signal fluctuations. These contributions may include head motions, the underling microvasculature anatomy and cellular morphology.

Electrophysiological correlates of the brain's intrinsic large-scale functional architecture

Spontaneous fluctuations in the blood-oxygen-level-dependent (BOLD) signals demonstrate consistent temporal correlations within large-scale brain networks associated with different functions. The neurophysiological correlates of this phenomenon remain elusive. Here, we show in humans that the slow cortical potentials recorded by electrocorticography demonstrate a correlation structure similar to that of spontaneous BOLD fluctuations across wakefulness, slow-wave sleep, and rapid-eye-movement sleep. Gamma frequency power also showed a similar correlation structure but only during wakefulness and rapid-eye-movement sleep. Our results provide an important bridge between the large-scale brain networks readily revealed by spontaneous BOLD signals and their underlying neurophysiology.

Simultaneous EEG/Functional Magnetic Resonance Imaging at 4 Tesla: Correlates of Brain Activity to Spontaneous Alpha Rhythm During Relaxation

: Simultaneous EEG and functional magnetic resonance imaging have been applied to the study of brain states associated with alpha waves using a magnetic field strength of 1.5 Tesla and has been shown in recent years to be feasible up to 3 Tesla for other applications. This study demonstrates this technique's continued viability at a field strength of 4 Tesla, affording a proportionally greater sensitivity to changes in Blood Oxygen Level Dependent (BOLD) signal. In addition, for the study of alpha correlations, the authors used a larger number of subjects and scanning sessions than in the previous work. Random effects group regression analysis of 35 EEG/functional magnetic resonance imaging sessions against occipital alpha magnitude in a relaxed state detected bilateral widespread activation of dorsal thalamus and portions of the anterior cingulate and cerebellum. In the same group analysis, deactivations arose predominantly in the fusiform and adjacent visual association areas with a small activation cluster also detected in dorsolateral prefrontal cortex. This pattern is consistent with a correspondence between alpha magnitude variations and resting state network dynamics ascertained by recent studies of low frequency spontaneous BOLD fluctuations. The central role of the thalamus in resting state networks correlated with alpha activity is highlighted. Demonstrating the applicability of simultaneous EEG/functional magnetic resonance imaging up to 4 Tesla is particularly important for clinically relevant research involving challenging spontaneous EEG abnormalities, such as those of epilepsy.

Spontaneous low-frequency blood oxygenation level-dependent fluctuations and functional connectivity analysis of the ‘resting’ brain

Functional magnetic resonance imaging techniques using the blood oxygenation level-dependent (BOLD) contrast are widely used to map human brain function by relating local hemodynamic responses to neuronal stimuli compared to control conditions. There is increasing interest in spontaneous cerebral BOLD fluctuations that are prominent in the low-frequency range (<0.1 Hz) and show intriguing spatio-temporal correlations in functional networks. The nature of these signal fluctuations remains unclear, but there is accumulating evidence for a neural basis opening exciting new avenues to study human brain function and its connectivity at rest. Moreover, an increasing number of patient studies report disease-dependent variation in the amplitude and spatial coherence of low-frequency BOLD fluctuations (LFBF) that may afford greater diagnostic sensitivity and easier clinical applicability than standard fMRI. The main disadvantage of this emerging tool relates to physiological (respiratory, cardiac and vasomotion) and motion confounds that are challenging to disentangle requiring thorough preprocessing. Technical aspects of functional connectivity fMRI analysis and the neuroscientific potential of spontaneous LFBF in the default mode and other resting-state networks have been recently reviewed. This review will give an update on the current knowledge of the nature of LFBF, their relation to physiological confounds and potential for clinical diagnostic and pharmacological studies.

Origin of Synchronized Low-Frequency Blood Oxygen Level–Dependent Fluctuations in the Primary Visual Cortex

Low-frequency (<0.08 Hz) fluctuations in spontaneous blood oxygen level-dependent (BOLD) signal intensity show synchronization across anatomically interconnected and functionally specific brain regions, suggesting a neural origin of fluctuations. To determine the mechanism by which high-frequency neural activity results in low-frequency BOLD fluctuations, I obtained measurements of the effects of neurovascular coupling on the frequency content of BOLD fluctuations. 3T recordings of BOLD signal intensity in the primary visual cortex were obtained in response to visual stimuli presented at varying temporal frequencies to determine which stimulus frequencies were successfully transmitted to BOLD signal intensity. Additional BOLD time series recordings were performed in a resting state and during natural visual stimulation, and frequencies comprising BOLD fluctuations were measured. Magnetoencephalographic (MEG) time series recordings were obtained in a resting state to measure which components of MEG signal intensity best correlated in frequency distribution to observed BOLD fluctuations. Visually driven oscillations in BOLD signal intensity were observed up to 0.2 Hz, representing a mismatch between low-pass filter properties of neurovascular coupling and observed frequencies of spontaneous BOLD fluctuations, which are <0.05 Hz in the primary visual cortex. Visual stimulation frequencies of >0.2 Hz resulted in frequency-dependent increases in mean BOLD response. Amplitude modulation of high-frequency neural activity was measured in MEG time series data, which demonstrated 1/frequency distribution with the greatest power comprising frequencies <0.05 Hz, consistent with the distribution of observed BOLD fluctuations. Synchronized low-frequency BOLD fluctuations likely arise from a combination of vascular low-pass filtering and low-frequency amplitude modulation of neural activity.

Correlations in spontaneous bold (blood oxygen level dependent) fluctuations differ depending on resting state condition

Correlations in spontaneous bold (blood oxygen level dependent) fluctuations differ depending on resting state condition

Loss of Resting Interhemispheric Functional Connectivity after Complete Section of the Corpus Callosum

Slow (<0.1 Hz), spontaneous fluctuations in the functional magnetic resonance imaging blood oxygen level-dependent (BOLD) signal have been shown to exhibit phase coherence within functionally related areas of the brain. Surprisingly, this phenomenon appears to transcend levels of consciousness. The genesis of coherent BOLD fluctuations remains to be fully explained. We present a resting state functional connectivity study of a 6-year-old child with a radiologically normal brain imaged both before and after complete section of the corpus callosum for the treatment of intractable epilepsy. Postoperatively, there was a striking loss of interhemispheric BOLD correlations with preserved intrahemispheric correlations. These unique data provide important insights into the relationship between connectional anatomy and functional organization of the human brain. Such observations have the potential to increase our understanding of large-scale brain systems in health and disease as well as improve the treatment of neurologic disorders.

Detecting spatiotemporal nonlinear dynamics in resting state of human brain based on fMRI datasets

In this work, a nonlinear dynamics method, coupled map lattices, was applied to functional magnetic resonance imaging (fMRI) datasets to examine the spatiotemporal properties of resting state blood oxygen level-dependent (BOLD) fluctuations. Spatiotemporal Lyapunov Exponent (SPLE) was calculated to study the deterministic nonlinearity in resting state human brain of nine subjects based on fMRI datasets. The results show that there is nonlinearity and determinism in resting state human brain. Furthermore, the results demonstrate that there is a spatiotemporal chaos phenomenon in resting state brain, and suggest that fluctuations of fMRI data in resting state brain cannot be fully attributed to nuclear magnetic resonance noise. At the same time, the spatiotemporal chaos phenomenon suggests that the correlation between voxels varies with time and there is a dynamic functional connection or network in resting state human brain.

Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: Implications for functional connectivity at rest

Recent studies have demonstrated large amplitude spontaneous fluctuations in functional-MRI (fMRI) signals in humans in the resting state. Importantly, these spontaneous fluctuations in blood-oxygenation-level-dependent (BOLD) signal are often synchronized over distant parts of the brain, a phenomenon termed functional-connectivity. Functional-connectivity is widely assumed to reflect interregional coherence of fluctuations in activity of the underlying neuronal networks. Despite the large body of human imaging literature on spontaneous activity and functional-connectivity in the resting state, the link to underlying neural activity remains tenuous. Through simultaneous fMRI and intracortical neurophysiological recording, we demonstrate correlation between slow fluctuations in BOLD signals and concurrent fluctuations in the underlying locally measured neuronal activity. This correlation varied with time-lag of BOLD relative to neuronal activity, resembling a traditional hemodynamic response function with peaks at approximately 6 s lag of BOLD signal. The correlations were reliably detected when the neuronal signal consisted of either the spiking rate of a small group of neurons, or relative power changes in the multi-unit activity band, and particularly in the local field potential gamma band. Analysis of correlation between the voxel-by-voxel fMRI time-series and the neuronal activity measured within one cortical site showed patterns of correlation that slowly traversed cortex. BOLD fluctuations in widespread areas in visual cortex of both hemispheres were significantly correlated with neuronal activity from a single recording site in V1. To the extent that our V1 findings can be generalized to other cortical areas, fMRI-based functional-connectivity between remote regions in the resting state can be linked to synchronization of slow fluctuations in the underlying neuronal signals.

Intrinsic brain activity in altered states of consciousness: how conscious is the default mode of brain function?

Spontaneous brain activity has recently received increasing interest in the neuroimaging community. However, the value of resting-state studies to a better understanding of brain-behavior relationships has been challenged. That altered states of consciousness are a privileged way to study the relationships between spontaneous brain activity and behavior is proposed, and common resting-state brain activity features observed in various states of altered consciousness are reviewed. Early positron emission tomography studies showed that states of extremely low or high brain activity are often associated with unconsciousness. However, this relationship is not absolute, and the precise link between global brain metabolism and awareness remains yet difficult to assert. In contrast, voxel-based analyses identified a systematic impairment of associative frontoparieto-cingulate areas in altered states of consciousness, such as sleep, anesthesia, coma, vegetative state, epileptic loss of consciousness, and somnambulism. In parallel, recent functional magnetic resonance imaging studies have identified structured patterns of slow neuronal oscillations in the resting human brain. Similar coherent blood oxygen level-dependent (BOLD) systemwide patterns can also be found, in particular in the default-mode network, in several states of unconsciousness, such as coma, anesthesia, and slow-wave sleep. The latter results suggest that slow coherent spontaneous BOLD fluctuations cannot be exclusively a reflection of conscious mental activity, but may reflect default brain connectivity shaping brain areas of most likely interactions in a way that transcends levels of consciousness, and whose functional significance remains largely in the dark.

Resting‐state functional connectivity of the rat brain

Regional-specific average time courses of spontaneous fluctuations in blood oxygen level dependent (BOLD) MRI contrast at 9.4T in lightly anesthetized resting rat brain are formed, and correlation coefficients between time course pairs are interpreted as measures of connectivity. A hierarchy of regional pairwise correlation coefficients (RPCCs) is observed, with the highest values found in the thalamus and cortex, both intra- and interhemisphere, and lower values between the cortex and thalamus. Independent sensory networks are distinguished by two methods: data driven, where task activation defines regions of interest (ROI), and hypothesis driven, where regions are defined by the rat histological atlas. Success in these studies is attributed in part to the use of medetomidine hydrochloride (Domitor) for anesthesia. Consistent results in two different rat-brain systems, the sensorimotor and visual, strongly support the hypothesis that resting-state BOLD fluctuations are conserved across mammalian species and can be used to map brain systems.

Mapping resting-state functional connectivity using perfusion MRI

Resting-state, low-frequency (<0.08 Hz) fluctuations of blood oxygenation level-dependent (BOLD) magnetic resonance signal have been shown to exhibit high correlation among functionally connected regions. However, correlations of cerebral blood flow (CBF) fluctuations during the resting state have not been extensively studied. The main challenges of using arterial spin labeling perfusion magnetic resonance imaging to detect CBF fluctuations are low sensitivity, low temporal resolution, and contamination from BOLD. This work demonstrates CBF-based quantitative functional connectivity mapping by combining continuous arterial spin labeling (CASL) with a neck labeling coil and a multi-channel receiver coil to achieve high perfusion sensitivity. In order to reduce BOLD contamination, the CBF signal was extracted from the CASL signal time course by high frequency filtering. This processing strategy is compatible with sinc interpolation for reducing the timing mismatch between control and label images and has the flexibility of choosing an optimal filter cutoff frequency to minimize BOLD fluctuations. Most subjects studied showed high CBF correlation in bilateral sensorimotor areas with good suppression of BOLD contamination. Root-mean-square CBF fluctuation contributing to bilateral correlation was estimated to be 29±19% (N=13) of the baseline perfusion, while BOLD fluctuation was 0.26±0.14% of the mean intensity (at 3 T and 12.5 ms echo time).

Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: implications for functional connectivity at rest

Event Abstract Back to Event Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: implications for functional connectivity at rest Amir Shmuel1* and D. A. Leopold2 1 MNI, McGill University, Canada 2 NIMH, NIH, United States Recent studies have demonstrated large amplitude spontaneous fluctuations in functional-MRI (fMRI) signals in humans in the resting state. Importantly, these spontaneous fluctuations in blood-oxygenation-level-dependent (BOLD) signal are often synchronized over distant parts of the brain, a phenomenon termed functional connectivity. Functional-connectivity is widely assumed to reflect interregional coherence of fluctuations in activity of the underlying neuronal networks. Despite the large body of human imaging literature on spontaneous activity and functional-connectivity in the resting state, the link to underlying neural activity remains tenuous. Through simultaneous fMRI and intracortical neurophysiological recording, we demonstrate correlation between slow fluctuations in BOLD signals and concurrent fluctuations in the underlying locally measured neuronal activity. This correlation varied with time-lag of BOLD relative to neuronal activity, resembling a traditional hemodynamic response function with peaks at 6 s lag of BOLD signal. The correlations were reliably detected when the neuronal signal consisted of either the spiking rate of a small group of neurons, or relative power changes in the multi-unit activity band, and particularly in the local field potential gamma band. Analysis of correlation between the voxel-by-voxel fMRI time-series and the neuronal activity measured within one cortical site showed patterns of correlation that slowly traversed cortex. BOLD fluctuations in widespread areas in visual cortex of both hemispheres were significantly correlated with neuronal activity from a single recording site in V1. To the extent that our V1 findings can be generalized to other cortical areas, fMRI-based functional-connectivity between remote regions in the resting state can be linked to synchronization of slow fluctuations in the underlying neuronal signals. Support: The data were obtained in the Lab of Nikos K. Logothetis (MPI für Biologische Kybernetik, Tübingen, Germany). Supported by NKL through funds of the Max Planck Society. AS was supported by a long term fellowship from the European Molecular Biology Organization. Conference: 10th International Conference on Cognitive Neuroscience, Bodrum, Turkey, 1 Sep - 5 Sep, 2008. Presentation Type: Oral Presentation Topic: Symposium 14: Multimodal Studies of Oscillations Citation: Shmuel A and Leopold DA (2008). Neuronal correlates of spontaneous fluctuations in fMRI signals in monkey visual cortex: implications for functional connectivity at rest. Conference Abstract: 10th International Conference on Cognitive Neuroscience. doi: 10.3389/conf.neuro.09.2009.01.067 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 01 Dec 2008; Published Online: 01 Dec 2008. * Correspondence: Amir Shmuel, MNI, McGill University, Montreal, QC, Canada, amir.shmuel@mcgill.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Amir Shmuel D. A Leopold Google Amir Shmuel D. A Leopold Google Scholar Amir Shmuel D. A Leopold PubMed Amir Shmuel D. A Leopold Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Reciprocal Effects of Antidepressant Treatment on Activity and Connectivity of the Mood Regulating Circuit: An fMRI Study

Reciprocal Effects of Antidepressant Treatment on Activity and Connectivity of the Mood Regulating Circuit: An fMRI Study

Regional coherence changes in the early stages of Alzheimer’s disease: A combined structural and resting-state functional MRI study

Recent functional imaging studies have indicated that the pathophysiology of Alzheimer’s disease (AD) can be associated with the changes in spontaneous low-frequency (<0.08 Hz) blood oxygenation level-dependent fluctuations (LFBF) measured during a resting state. The purpose of this study was to examine regional LFBF coherence patterns in early AD and the impact of regional brain atrophy on the functional results. Both structural MRI and resting-state functional MRI scans were collected from 14 AD subjects and 14 age-matched normal controls. We found significant regional coherence decreases in the posterior cingulate cortex/precuneus (PCC/PCu) in the AD patients when compared with the normal controls. Moreover, the decrease in the PCC/PCu coherence was correlated with the disease progression measured by the Mini-Mental State Exam scores. The changes in LFBF in the PCC/PCu may be related to the resting hypometabolism in this region commonly detected in previous positron emission tomography studies of early AD. When the regional PCC/PCu atrophy was controlled, these results still remained significant but with a decrease in the statistical power, suggesting that the LFBF results are at least partly explained by the regional atrophy. In addition, we also found increased LFBF coherence in the bilateral cuneus, right lingual gyrus and left fusiform gyrus in the AD patients. These regions are consistent with previous findings of AD-related increased activation during cognitive tasks explained in terms of a compensatory-recruitment hypothesis. Finally, our study indicated that regional brain atrophy could be an important consideration in functional imaging studies of neurodegenerative diseases.

Handedness-related functional connectivity using low-frequency blood oxygenation level-dependent fluctuations

Functional neuroimaging studies of handedness have traditionally focused on exploring regionally activated discrepancies, yet little is known regarding the effect of handedness on functional connections of brain regions. Here, we reported the relationship between cerebellar functional connectivity patterns and handedness by low-frequency blood oxygenation level-dependent fluctuations. Compared with the right-handers, the left-handers show higher cerebellar-prefrontal, cerebellar-parietal, and cerebellar-temporal functional connectivity, and lower cerebellar-limbic connectivity. Previous non-human primate studies have shown that these regions with known contributions to higher cognitive functions have afferent or efferent connections with the cerebellum. Our findings suggest that these observed low-frequency fluctuation correlations may reflect actually anatomic connections between the cerebellum and cerebral cortex, and the cerebellar involvement in higher function may be associated with handedness.