Fractional amplitude of low-frequency fluctuation changes in monkeys with spinal cord injury: A resting-state fMRI study

Purpose

Although functional magnetic resonance imaging (fMRI) has revealed that spinal cord injury (SCI) causes anomalous changes in task-induced brain activation, its effect during the resting state remains unclear. The aim of this study is to explore the changes of the brain resting-state function in non-human primates with unilateral SCI.

Materials and methods

Eleven adult female rhesus monkeys were subjected to resting-state fMRI: five with unilateral thoracic SCI and six healthy monkeys, to obtain the fractional amplitude of low-frequency fluctuations (fALFF) of the blood oxygenation level-dependent (BOLD) contrast signal to determine the influence of SCI on the cerebral resting-state function.

Results

The SCI-induced fALFF vary significantly in several encephalic regions, including the left cerebellum, the left thalamus, the right lateral geniculate nucleus, the right superior parietal lobule, and the posterior cingulate gyrus.

Conclusion

Analysis of the resting-state fMRI provides evidence of abnormal spontaneous brain activations in primates with SCI, which may help us understand the pathophysiologic mechanisms underlying the changes in neural plasticity in the central nervous system after SCI.     

结合局部一致性和低频振幅探究躯体症状障碍患者大脑自发性活动的改变

躯体症状障碍（somatic symptom disorder,SSD）是一种常见的医学疾病,致病原因涉及生物学、心理学及社会因素.目前关于SSD的神经机制知之甚少.本研究通过静息态功能磁共振成像（functional magnetic resonance imaging,fMRI）,结合低频振幅（amplitudes of low-frequency fluctuation,ALFF）和局部一致性（regional homogeneity,ReHo）分析探究45位SSD患者和43位健康对照自发性脑活动特征的区别.结果发现：与对照组相比,SSD患者右侧扣带回中部的ReHo值显著升高,而右侧楔前叶、左侧颞下回延伸到左侧颞中回和左侧海马旁回、右侧脑桥的ReHo值显著降低.同时,SSD患者扣带回中部延伸至左侧额中回、右侧脑岛延伸至右侧额下回、左侧额中回延伸至左侧前扣带回的ALFF值均显著升高.这些脑区的脑功能与自我加工、情绪处理、身体知觉等有关,与SSD发病机制有重要联系.     

fMRI assessment of thalamocortical connectivity during attentional performance

Functional magnetic resonance imaging (fMRI) studies have shown dysfunction in key areas associated with the thalamocortical circuit in patients with schizophrenia. This study examined the functional connectivity involving the frontal-thalamic circuitry during a spatial focusing-of-attention task in 18 unmedicated patients with schizophrenia and 38 healthy controls. Functional connectivity was analyzed by assigning seed regions (in the thalamic nuclei (mediodorsal nucleus (MDN), pulvinar, anterior nucleus (AN)), the dorsolateral prefrontal cortex (Brodmann areas 9 and 46), and the caudate), and correlating their respective activity with that in the non-seed regions voxel-wise. Functional connectivity analysis demonstrated that functional connectivity was significantly impaired in patients, e.g., between the right pulvinar and regions such as the prefrontal and temporal cortices and the cerebellum. On the other hand, enhanced functional connectivity was found in patients e.g., between the AN and regions such as the prefrontal and temporal cortices. In addition, the patients had significantly lower task performance and less (but non-significant) brain activation than those of controls. These results revealed disturbed functional integration in schizophrenia, and suggested that the functional connectivity abnormalities in the thalamocortical circuitry, especially the frontal-thalamic circuitry, may underlie the attention deficits in schizophrenia patients. Further, this study suggested that functional connectivity analysis might be more sensitive than brain activation analysis in detecting the functional abnormalities in schizophrenia.     

Neural correlates of a clinical continuous performance test

Functional magnetic resonance imaging (fMRI) was performed in 30 healthy adults to identify the location, magnitude, and extent of activation in brain regions that are engaged during the performance of Conners' Continuous Performance Test (CPT). Performance on the task during fMRI was highly correlated with performance on the standard Conners' CPT in the behavioral testing laboratory. An extensive neural network was activated during the task that included the frontal, cingulate, parietal, temporal, and occipital cortices; the cerebellum and the basal ganglia. There was also a network of brain regions which were more active during fixation than task. The magnitude of activation in several regions was correlated with reaction time. Among regions that were more active during task, the overall volume of supratentorial activation and cerebellar activation was greater in the left hemisphere. Frontal activation was greater in dorsal than in ventral regions, and dorsal frontal activation was bilateral. Ventral frontal region and parietal lobe activation were greater in the right hemisphere. The volume of clusters of activation in the extrastriate ventral visual pathway was greater in the left hemisphere. This network is consistent with existing models of motor control, visual object processing and attentional control and may serve as a basis for hypothesis-driven fMRI studies in clinical populations with deficits in Conners' CPT performance.     

The anxiolytic effects of midazolam during anticipation to pain revealed using fMRI

BACKGROUND AND PURPOSE: Functional neuroimaging can distinguish components of the pain experience associated with anticipation to pain from those associated with the experience of pain itself. Anticipation to pain is thought to increase the suffering of chronic pain patients. Inappropriate anxiety, of which anticipation is a component, is also a cause of disability. We present a pharmacological functional magnetic resonance imaging (fMRI) study in which we investigate the selective modulation by midazolam of brain activity associated with anticipation to pain compared to pain itself. METHODS: Eight right-handed male volunteers underwent fMRI combined with a thermal pain conditioning paradigm and midazolam (30 mug/kg) or saline administration on different occasions, with order randomized across volunteers. Volunteers learned to associate a colored light with either painful, hot stimulation or nonpainful, warm stimulation to the back of the left hand. RESULTS: Comparison of the period during thermal stimulation (pain-warm) revealed a network of brain activity commonly associated with noxious stimulation, including activities in the anterior cingulate cortex (ACC), the bilateral insular cortices (anterior and posterior), the thalamus, S1, the motor cortex, the brainstem, the prefrontal cortex and the cerebellum. Comparison of the periods preceding thermal stimulation (anticipation to pain-anticipation to warm) revealed activity principally in the ACC, the contralateral anterior insular cortex and the ipsilateral S2/posterior insula. Detected by a region-of-interest analysis, midazolam reduced the activity associated specifically with anticipation to pain while controlling for anticipation to warm. This was most significant in the contralateral anterior insula (P<.05). There were no significant drug effects on the activity associated with pain itself. CONCLUSION: In identifying a pharmacological effect on activity preceding but not during pain, we have successfully demonstrated an fMRI assay that can be used to study the action of anxiolytic agents in a relatively small cohort of humans.     

Investigating directed influences between activated brain areas in a motor-response task using fMRI

Localization of cognitive processes is a strength of functional neuroimaging. However, information about functional interactions between brain areas is crucial for a deeper understanding of brain function. We applied vector autoregressive modeling in the context of Granger causality as a method to analyze directed connectivity in a standard event-related fMRI study using a simple auditory-motor paradigm. The basic idea is to use temporal information in stochastic time series of a brain region in order to predict signal time courses in other brain regions. Thus, we predicted that the method should demonstrate causal influence of the auditory cortex and the supplementary motor area (SMA) on primary motor cortex. Eleven right-handed healthy female subjects were instructed to press a ball with either their left or their right hand when hearing the command "left" or "right" in the scanner. Influence to the left motor cortex was found from bilateral auditory cortex as well as from the SMA in 9 of 11 subjects. Granger causality to the right motor cortex existed from bilateral auditory cortex in 5 and from SMA in 6 subjects. Granger causality to the SMA existed from right auditory cortex in 7 subjects and from left auditory cortex in 8 subjects. Our findings in a simple task show that even under suboptimal circumstances (a relatively long TR of 2440 ms), Granger causality can be a useful tool to explore effective connectivity. Temporally optimized scanning should increase that potential.     

Low-frequency signal changes reflect differences in functional connectivity between good readers and dyslexics during continuous phoneme mapping

The current fMRI study investigated correlations of low-frequency signal changes in the left inferior frontal gyrus, right inferior frontal gyrus and cerebellum in 13 adult dyslexic and 10 normal readers to examine functional networks associated with these regions. The extent of these networks to regions associated with phonological processing (frontal gyrus, occipital gyrus, angular gyrus, inferior temporal gyrus, fusiform gyrus, supramarginal gyrus and cerebellum) was compared between good and dyslexic readers. Analysis of correlations in low-frequency range showed that regions known to activate during an "on-off" phoneme-mapping task exhibit synchronous signal changes when the task is administered continuously (without any "off" periods). Results showed that three functional networks, which were defined on the basis of documented structural deficits in dyslexics and included regions associated with phonological processing, differed significantly in spatial extent between good readers and dyslexics. The methodological, theoretical and clinical significance of the findings for advancing fMRI research and knowledge of dyslexia are discussed.     

Characterization of BOLD-fMRI signal during a verbal fluency paradigm in patients with intracerebral tumors affecting the frontal lobe

Previous studies have indicated that the BOLD-fMRI signal can be modified by tumor processes in close vicinity to functional brain areas. This effect has been investigated primarily for the perirolandic area but there is only a limited number of studies concerning frontal cortical regions. Therefore, the aim of the current study was to characterize BOLD-fMRI signal and activation patterns in patients with frontal brain tumors while performing a verbal fluency task. Six patients (ages 31-56 years) suffering from frontal (5 left sided and 1 right sided) intracerebral tumors were examined with fMRI while performing a verbal fluency task in a blocked paradigm design. Eight healthy volunteers served as the control group. The patients (5 right and 1 left handed) demonstrated left frontal activation which could be clearly located outside the tumor area and adjacent edema with varying degrees of additional right frontal activation. In the predominant left frontal activation cluster, the mean voxel based z-score and cluster size were not statistically different between patients and controls. The present fMRI study is indicating that language related BOLD signal changes in the frontal cortex of patients with tumors close to functional areas were comparable to the signal in normal controls. Additionally, the temporal hemodynamic response characteristic was comparable in both groups. This is an important finding consistent with PET results and corroborates the feasibility of functional mapping approaches in patients with tumors affecting the frontal lobe. Additional studies investigating alterations of the hemodynamic response depending on tumor location and histology are required in order to further elucidate the association between pathophysiology and BOLD fMRI signal.     

Functional MRI changes in the central motor system in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a multisystemic disease involving multiple organ systems including central nervous system (CNS) and muscles. Few studies have focused on the central motor system in DM1, pointing to a subclinical abnormality in the CNS. The aim of our study was to investigate patterns of cerebral activation in DM1 during a motor task using functional MRI (fMRI). Fifteen DM1 patients, aged 20 to 59 years, and 15 controls of comparable age were scanned during a self-paced sequential finger-to-thumb opposition task of their dominant right hand. Functional MRI images were analyzed using SPM99. Patients underwent clinical and genetic assessment; all subjects underwent a conventional MR study. Myotonic dystrophy type 1 patients showed greater activation than controls in bilateral sensorimotor areas and inferior parietal lobules, basal ganglia and thalami, in the ipsilateral premotor area, insula and supplementary motor area (corrected P<.05). Analysis of the interaction between disease and age showed that correlation with age was significantly greater in patients than in controls in bilateral sensorimotor areas and in contralateral parietal areas. Other clinical and MR characteristics did not correlate with fMRI. Functional changes in DM1 may represent compensatory mechanisms such as reorganization and redistribution of functional networks to compensate for ultrastructural and neurochemical changes occurring as part of the accelerated aging process.     

A comparison of Gamma and Gaussian dynamic convolution models of the fMRI BOLD response

Blood oxygenation level-dependent (BOLD) contrast-based functional magnetic resonance imaging (fMRI) has been widely utilized to detect brain neural activities and great efforts are now stressed on the hemodynamic processes of different brain regions activated by a stimulus. The focus of this paper is the comparison of Gamma and Gaussian dynamic convolution models of the fMRI BOLD response. The convolutions are between the perfusion function of the neural response to a stimulus and a Gaussian or Gamma function. The parameters of the two models are estimated by a nonlinear least-squares optimal algorithm for the fMRI data of eight subjects collected in a visual stimulus experiment. The results show that the Gaussian model is better than the Gamma model in fitting the data. The model parameters are different in the left and right occipital regions, which indicate that the dynamic processes seem different in various cerebral functional regions.     

Occipital-parietal interactions during shifts of exogenous visuospatial attention: trial-dependent changes of effective connectivity

We studied neural interactions between brain areas involved in exogenous (stimulus-driven) control of visuospatial attention. With event-related functional magnetic resonance imaging (fMRI), we investigated changes of connectivity during shifts of spatial attention from an attended location to a previously unattended target location. Using a 3-T scanner, fMRI data were acquired from three healthy volunteers. According to a central visual cue, participants directed endogenous spatial attention to the left or the right visual hemifield for blocks of 56 s. Peripheral visual targets were presented unpredictably in either the attended hemifield (valid trials, 80%) or in the unattended hemifield (invalid trials, 20%) and participants performed a two-alternative forced-choice discrimination task with the target, irrespective of cue validity. In accordance with previous results, we found that the temporal–parietal junction (TPJ) mediates the shift of spatial attention toward stimuli presented at the unattended side (i.e., invalid trials). We critically studied the interaction between occipital areas responding to the visual stimuli and other brain regions in order to find regions functionally coupled with the occipital cortex during invalid trials. We found that the coupling between occipital areas processing visual stimuli and the TPJ selectively increased during invalid trials. Our results highlight how changes of connectivity between brain areas can describe attentional processes such as stimulus-driven shifts of spatial attention.     

Steady-state activation in somatosensory cortex after changes in stimulus rate during median nerve stimulation

Passive electrical stimulation activates various human somatosensory cortical systems including the contralateral primary somatosensory area (SI), bilateral secondary somatosensory area (SII) and bilateral insula. The effect of stimulation frequency on blood oxygenation level-dependent (BOLD) activity remains unclear. We acquired 3-T functional magnetic resonance imaging (fMRI) in eight healthy volunteers during electrical median nerve stimulation at frequencies of 1, 3 and 10 Hz. During stimulation BOLD signal changes showed activation in the contralateral SI, bilateral SII and bilateral insula. Results of fMRI analysis showed that these areas were progressively active with the increase of rate of stimulation. As a major finding, the contralateral SI showed an increase of peak of BOLD activation from 1 to 3 Hz but reached a plateau during 10-Hz stimulation. Our finding is of interest for basic research and for clinical applications in subjects unable to perform cognitive tasks in the fMRI scanner.     

Aberrant resting-state cerebral blood flow and its connectivity in primary dysmenorrhea on arterial spin labeling MRI

PurposeThis study aimed to clarify the resting-state cerebral blood flow alteration patterns induced by primary dysmenorrhea, investigate the relationships between cerebral blood flow alterations and clinical parameters of patients with primary dysmenorrhea, and explore whether brain regions with abnormal cerebral blood flow also feature functional connectivity changes.MethodsArterial spin labeling imaging and clinical parameters were acquired in 42 patients with primary dysmenorrhea and 41 healthy controls during their menstrual phases. Differences in cerebral blood flow were compared between the two groups, and the clusters with significant group differences were selected as the regions of interest for further statistical analyses.ResultsCompared to healthy controls, patients with primary dysmenorrhea exhibited increased cerebral blood flow in the bilateral precuneus, left posterior cingulate cortex, and right rolandic operculum. Among patients with primary dysmenorrhea, we identified a negative correlation between the cerebral blood flow in the right rolandic operculum and the visual analogue score for anxiety, and greater correlation between the functional connectivity in the precuneus/posterior cingulate cortex and the right middle cingulate cortex, and between the right rolandic operculum and the left inferior parietal lobule and the bilateral postcentral gyrus.DiscussionCerebral blood flow abnormalities associated with primary dysmenorrhea were mainly concentrated in the areas comprising the default mode network in primary dysmenorrhea patients, which could be involved in the central mechanism of primary dysmenorrhea. Cerebral blood flow alteration in the rolandic operculum may underlie an anxiety-induced compulsive tendency in patients with primary dysmenorrhea. Investigating the enhanced connectivity among various pain-related brain regions could improve understanding of the onset and development of primary dysmenorrhea.     

The Progress of the Gait Impairment and Brain Activation in a Patient with Post-stroke Hemidystonia

Objective: We explore the effects of body weight-supported (BWS) treadmill training, including the change of cortical activation, on a patient with post-stroke hemidystonia. Patient: The patient was a 71-year-old man with left thalamus hemorrhage. His motor symptoms indicated slight impairment. There was no overactive muscle contraction in the supine, sitting, or standing positions. During his gait, the right initial contact was the forefoot, and his right knee showed an extension thrust pattern. These symptoms suggested that he had post-stroke hemidystonia. Methods: The patient performed BWS treadmill training 14 times over 3 weeks. The effects of the BWS training were assessed by a step-length analysis, electromyography and functional magnetic resonance imaging (fMRI). Results: The patient''s nonparetic step length was extended significantly in the Inter-BWS (p<0.001) and Post-BWS (p=0.025) periods compared to the Pre-BWS session. The excessive muscle activity of the right gastrocnemius medialis in the swing phase was decreased at the Inter-BWS, Post-BWS, and follow-up compared to the Pre-BWS session. The peak timing difference of the bilateral tibialis anterior muscle became significant (p<0.05) on the first day of the intervention. The fMRI revealed that the cortical areas activated by the motor task converged through the intervention (p<0.05, family-wise error corrected). Conclusion: These results suggest that there was improvement of the patient''s symptoms of post-stroke hemidystonia due to changes in the brain activity during voluntary movement after BWS intervention. Body weight-supported treadmill training may thus be an effective treatment for patients with poststroke hemidystonia.     

Functional MRI and multivariate autoregressive models

Connectivity refers to the relationships that exist between different regions of the brain. In the context of functional magnetic resonance imaging (fMRI), it implies a quantifiable relationship between hemodynamic signals from different regions. One aspect of this relationship is the existence of small timing differences in the signals in different regions. Delays of 100 ms or less may be measured with fMRI, and these may reflect important aspects of the manner in which brain circuits respond as well as the overall functional organization of the brain. The multivariate autoregressive time series model has features to recommend it for measuring these delays and is straightforward to apply to hemodynamic data. In this review, we describe the current usage of the multivariate autoregressive model for fMRI, discuss the issues that arise when it is applied to hemodynamic time series and consider several extensions. Connectivity measures like Granger causality that are based on the autoregressive model do not always reflect true neuronal connectivity; however, we conclude that careful experimental design could make this methodology quite useful in extending the information obtainable using fMRI.     

Diffusion-weighted imaging features of brain in obesity

PURPOSE: Obesity is characterized by an altered distribution of body fluid. However, distribution of fluid (extracellular/intracellular) in brain tissues has not been studied in obese subjects yet. The purpose of this study was to detect possible brain diffusion changes especially in satiety and hunger related centers in obese subjects by diffusion weighted imaging (DWI). METHODS: Conventional MRI and DWI of the brain was obtained from 81 obese patients (obese=68, morbid obese=13) and 29 age-matched, nonobese. The apparent diffusion coefficient (ADC) values were calculated in hypothalamus; amygdala; hippocampal gyrus; thalamus; insula; cingulate gyrus; orbitofrontal, dorsomedial and dorsolateral frontal, middle temporal and occipital cortex; cerebellum; midbrain and corpus striatum. RESULTS: The ADC values of hypothalamus, hippocampal gyrus, amygdala, insula, cerebellum and midbrain were significantly increased in patients (n:81) when compared to nonobese subjects. The ADC values of thalamus, hippocampal gyrus, amygdala, orbitofrontal, occipital, dorsolateral and middle temporal cortex, insula and midbrain were significantly increased in morbid obese when compared to nonobese subjects. The ADC values of orbitofrontal and occipital cortex were significantly higher in morbid obese than the values in the obese. The body mass index positively correlated with ADC values of amygdala, insula, orbitofrontal and middle temporal cortex. CONCLUSION: We observed increased ADC values of distinct locations related to satiety and hunger that suggest altered fluid distribution and/or vasogenic edema in obese subjects. Awareness of this abnormalities in brain tissue composition/function in obesity may contribute to better understanding of the underlying mechanisms.     

Investigation of the large-scale functional brain networks modulated by acupuncture

Previous neuroimaging studies have primarily focused on the neural activities involving the acute effects of acupuncture. Considering that acupuncture can induce long-lasting effects, several researchers have begun to pay attention to the sustained effects of acupuncture on the resting brain. Most of these researchers adopted functional connectivity analysis based on one or a few preselected brain regions and demonstrated various function-guided brain networks underlying the specific effect of acupuncture. Few have investigated how these brain networks interacted at the whole-brain level. In this study, we sought to investigate the functional correlations throughout the entire brain following acupuncture at acupoint ST36 (ACUP) in comparison with acupuncture at nearby nonacupoint (SHAM). We divided the whole brain into 90 regions and constructed functional brain network for each condition. Then we examined the network hubs and identified statistically significant differences in functional correlations between the two conditions. Following ACUP, but not SHAM, the limbic/paralimbic regions such as the amygdala, hippocampus and anterior cingulate gyrus emerged as network hubs. For direct comparisons, increased correlations for ACUP compared to SHAM were primarily related with the limbic/paralimbic and subcortical regions such as the insula, amygdala, anterior cingulate gyrus, and thalamus, whereas decreased correlations were mainly related with the sensory and frontal cortex. The heterogeneous modulation patterns between the two conditions may relate to the functional specific modulatory effects of acupuncture. The preliminary findings may help us to better understand the long-lasting effects of acupuncture on the entire resting brain, as well as the neurophysiological mechanisms underlying acupuncture.     

Aberrant default mode network in subjects with amnestic mild cognitive impairment using resting-state functional MRI

Amnestic mild cognitive impairment (aMCI) is a syndrome associated with faster memory decline than normal aging and frequently represents the prodromal phase of Alzheimer's disease. When a person is not actively engaged in a goal-directed task, spontaneous functional magnetic resonance imaging (fMRI) signals can reveal functionally connected brain networks, including the so-called default mode network (DMN). To date, only a few studies have investigated DMN functions in aMCI populations. In this study, group-independent component analysis was conducted for resting-state fMRI data, with slices acquired perpendicular to the long axis of the hippocampus, from eight subjects with aMCI and eight normal control subjects. Subjects with aMCI showed an increased DMN activity in middle cingulate cortex, medial prefrontal cortex and left inferior parietal cortex compared to the normal control group. Decreased DMN activity for the aMCI group compared to the normal control group was noted in lateral prefrontal cortex, left medial temporal lobe (MTL), left medial temporal gyrus, posterior cingulate cortex/retrosplenial cortex/precuneus and right angular gyrus. Although MTL volume difference between the two groups was not statistically significant, a decreased activity in left MTL was observed for the aMCI group. Positive correlations between the DMN activity and memory scores were noted for left lateral prefrontal cortex, left medial temporal gyrus and right angular gyrus. These findings support the premise that alterations of the DMN occur in aMCI and may indicate deficiencies in functional, intrinsic brain architecture that correlate with memory function, even before significant MTL atrophy is detectable by structural MRI.     

Disrupted functional connectivity in social anxiety disorder: a resting-state fMRI study

Dysfunction of the corticolimbic circuitry has been highlighted in social anxiety disorder (SAD) during social stimuli. However, few studies have investigated functional connectivity in SAD during the resting state, which may improve our understanding of SAD pathophysiology. The aim of this study was to investigate whether whole-brain functional connectivity might be aberrant in SAD patients, and if so, whether these changes are related to the measured clinical severity. Seventeen SAD patients and 19 healthy controls participated in resting-state functional magnetic resonance imaging. The brain was first divided into 90 paired brain regions and functional connectivity was then estimated by temporal correlation between each of these regions. Furthermore, connections that were significantly disrupted in SAD patients were correlated with clinical severity measured using the Liebowitz Social Anxiety Scale. Compared with healthy controls, SAD patients showed decreased positive connections within the frontal lobe and decreased negative connections between the frontal and occipital lobes. In particular, the weaker negative connections between the frontal lobe, which mainly involved the right median prefrontal cortex, and the occipital lobe had a significant positive correlation with the severity of SAD symptoms. The results support the hypothesis that some abnormalities of functional connectivity exist in SAD patients, which relate to the frontal cortex and occipital cortex. In addition, decreased functional connectivity between the frontal and occipital lobes and within the frontal lobe might be related to abnormal information processing and reflect disturbed neural organization resulting in defective social cognition, which could represent an early imaging biomarker for SAD.     

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.