Resting-state fMRI coherence is selectively diminished around 0.1 Hz in patients with unilateral carotid artery stenosis.

Very low frequency blood oxygen level dependent (BOLD) fluctuations have emerged as a valuable tool for describing brain anatomy, neuropathology, and development. Such fluctuations exhibit power law frequency dynamics, with largest amplitude at lowest frequencies. The biophysical mechanisms generating such fluctuations are poorly understood. Using publicly available data from 1019 subjects of age 7-30, we show that BOLD fluctuations exhibit temporal complexity that is linearly related to local connectivity (regional homogeneity), consistently and significantly covarying across subjects and across gray matter regions. This relationship persisted independently of covariance with gray matter density or standard deviation of BOLD signal. During late neurodevelopment, BOLD fluctuations were unchanged with age in association cortex while becoming more random throughout the rest of the brain. These data suggest that local interconnectivity may play a key role in establishing the complexity of low frequency BOLD fluctuations underlying functional MRI connectivity. Stable low frequency power dynamics may emerge through segmentation and integration of connectivity during development of distributed large-scale brain networks.

Caffeine increases the temporal variability of resting-state BOLD connectivity in the motor cortex

Recent evidence has demonstrated that unilateral carotid artery stenosis (CAS) can contribute to the development of cognitive impairment. However, the features of cognitive dysfunction induced by unilateral CAS remain unclear. Sixty asymptomatic patients with unilateral CAS were divided into mild, moderate and severe stenosis groups. These patients and 20 healthy controls provided clinical data and serum, which was used to assess the levels of certain vascular risk factors. Then, they participated in a battery of neuropsychological tests. Additionally, all participants underwent a 3.0 T magnetic resonance imaging (MRI) scan of the brain. Chi-square tests and one-way ANOVA were used to determine significant differences in the risk factors and cognitive test scores between groups. Multiple logistic regression analysis and the receiver operating characteristic (ROC) curve analysis were performed to identify the independent risk factors for cognitive impairment in patients with CAS. Finally, fluid attenuated inversion recovery (FLAIR) T1-weighted MRI images were processed by voxel-based morphometry (VBM) analysis using the Statistical Parametric Mapping (SPM) 8 software. Compared with healthy controls, the scores of the Mini-Mental State Examination, Digital Span Test backward, and Rapid Verbal Retrieve were significantly reduced in patients with left CAS. The scores in all cognitive scales were significantly lower in patients with right CAS than in controls. Logistic regression analysis demonstrated that the degree of carotid stenosis was an independent risk factor for cognitive impairment in asymptomatic patients with unilateral CAS. Furthermore, VBM analysis showed that, compared with those in healthy controls, gray matter and white matter volumes in specific brain areas were markedly decreased in patients with severe unilateral CAS. However, in patients with moderate right CAS, there was a significant decline in the volume of gray matter in the left parahippocampal gyrus and supplementary motor area. Additionally, the volume of white matter in the left insula was obviously lower in patients with moderate right CAS than in healthy controls. Unilateral asymptomatic CAS, especially on the right side, contributed to cognitive impairment, including memory, language, attention, executive function and visuospatial function. In addition, based on VBM analysis, both gray matter atrophy and white matter lesions were found in patients with unilateral asymptomatic CAS.

Consistent, high-quality data is key to the success of fMRI studies given the many confounding factors and undesired signals that contaminate these data. Several quality assurance (QA) metrics exist for fMRI (e.g., temporal signal-to-noise ratio (TSNR), percent ghosting, motion estimates), but none of them leverage relationships between echoes that are part of multi-echo (ME) fMRI acquisitions. Here, we fill this gap by proposing a new QA metric for for ME-fMRI that quantifies the likelihood a given ME scan is dominated by BOLD (Blood Oxygenation Level-Dependent) fluctuations. We refer to this metric aspBOLD; the probability of the signal change being primarily BOLD contrast-dominated. Having an estimate of overall BOLD weighting – both before and after preprocessing - is meaningful because BOLD is the intrinsic contrast mechanism used in fMRI to infer neural activity. We introducepBOLDto the neuroimaging community by first describing the theoretical principles supporting the metric. Next, we validatepBOLDefficacy using a small dataset (N=7 scans) of constant- and cardiac-gated scans that have distinct levels of contributing BOLD fluctuations. Third, we applypBOLDto a larger publicly available ME dataset (N=439 scans), to evaluate six different pre-processing pipelines, and show howpBOLDprovides complementary information to TSNR. Our results show that ME-based denoising increases bothpBOLDand TSNR relative to basic denoising; however, including the global signal (GS) as a regressor only improves TSNR, but worsenspBOLD. Further analyses looking at the BOLD-like characteristics of the GS and its relationship to cardiac and respiratory traces suggest that the observed decrease inpBOLDis likely due to a decrease in BOLD fluctuations of neural origin contributing to the GS, and not due to contributions from other physiological BOLD fluctuations (i.e., respiratory and cardiac function). Finally, we also demonstrate howpBOLDcan be applied as a data quality metric, by showing how higherpBOLDresults in better ability to predict phenotypes based on whole-brain functional connectivity matrices.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

We investigated the effects of resting state type on blood oxygen level-dependent (BOLD) signal and functional connectivity in two paradigms: participants either alternated between fixation and eyes closed or maintained fixation or eyes closed throughout each scan. The BOLD signal and functional connectivity of lower and higher tiers of the visual cortical hierarchy were found to be differentially modulated during eyes closed versus fixation. Fixation was associated with greater mean BOLD signals in primary visual cortex and lower mean BOLD signals in extrastriate visual areas than periods of eyes closed. In addition, analysis of thalamocortical functional connectivity during scans in which participants maintained fixation showed synchronized BOLD fluctuations between those thalamic nuclei whose mean BOLD signal was systematically modulated during alternating epochs of eyes closed and fixation, primary visual cortex and the attention network, while during eyes closed negatively correlated fluctuations were seen between the same thalamic nuclei and extrastriate visual areas. Finally, in all visual areas the amplitude of spontaneous BOLD fluctuations was greater during eyes closed than during fixation. The dissociation between early and late tiers of visual cortex, which characterizes both mean and functionally connected components of the BOLD signal, may depend on the reorganization of thalamocortical networks. Since dissociated changes in local blood flow also characterize transitions between different stages of sleep and wakefulness (Braun AR, Balkin TJ, Wesenten NJ, Gwadry F, Carson RE, Varga M, Baldwin P, Belenky G, Herscovitch P. Science 279: 91-95, 1998), our results suggest that dissociated endogenous neural activity in primary and extrastriate cortex may represent a general aspect of brain function.

Temporal correlations in low frequency BOLD fluctuations reveal functional networks

In the human brain, default mode network BOLD deactivations can be accompanied by both increases and decreases in glucose metabolism, depending on the respective metabolic demands of task-positive cognitive control and attention networks.

Mapping resting-state functional connectivity using perfusion MRI

BackgroundAltered fluctuations in blood oxygen level dependent (BOLD) signal during resting‐state functional magnetic resonance imaging (rs‐fMRI) have been considered indicative of decreased cerebrovascular health. Previous studies reported changes in BOLD fluctuations associated with Alzheimer’s dementia (AD) and white matter hyperintensities (WMH). However, to date, there has been no large‐scale study involving patients with AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and control subjects (CON) that has explored local AD‐ and WMH‐related effects in BOLD fluctuations.MethodWe calculated the voxel‐based coefficient of variation (CV: standard deviation divided by the mean) and the relative CV (rCV: CV divided by the mean CV of the whole‐brain) of the rs‐fMRI BOLD signal in the large multicentric DZNE DELCODE cohort. After spatial preprocessing, regression of movement parameters, movement spikes, and scanner drift, low‐pass filtering and exclusion of subjects with high motion, CV and rCV maps were obtained and compared with respect to (A) clinical diagnosis (AD: n = 79; MCI: n = 113; SCD: n = 314; CON: n = 192) and cerebrospinal fluid Aß42/40 (AD: n = 41; MCI: n = 64; SCD: n = 139; CON: n = 77); and (B) effects of vascular‐related lesions, here WMH.ResultThe CV and rCV of the precuneus and middle cingulum indicated increasingly reduced BOLD fluctuation across the clinical groups towards AD. Interestingly, we observed increases in rCV in the basal ganglia and frontal white matter in AD compared with CON. Of note, lower CSF Aß42/40 (more pathological) was associated to reduced CV and rCV in the precuneus and with lower rCV in the right angular gyrus. Subjects with higher WMH volume showed widespread reductions of CV in white matter near the left angular gyrus and reduced rCV in large portions of white matter and subcortical gray matter.ConclusionThe AD spectrum exhibits altered BOLD fluctuations that are at least partially tied to actual amyloid differences. Larger WMH are associated with reduced BOLD signal fluctuations consistent with widespread white matter pathology ‐ beyond the effects of diagnosis. We argue that rCV is a useful complement to CV to detect these changes that might reflect cerebrovascular impairment.

BackgroundAltered fluctuations in blood oxygen level dependent (BOLD) signal during resting‐state functional magnetic resonance imaging (rs‐fMRI) have been considered indicative of decreased cerebrovascular health. Previous studies reported changes in BOLD fluctuations associated with Alzheimer’s dementia (AD) and white matter hyperintensities (WMH). However, to date, there has been no large‐scale study involving patients with AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and control subjects (CON) that has explored local AD‐ and WMH‐related effects in BOLD fluctuations.MethodWe calculated the voxel‐based coefficient of variation (CV: standard deviation divided by the mean) and the relative CV (rCV: CV divided by the mean CV of the whole‐brain) of the rs‐fMRI BOLD signal in the large multicentric DZNE DELCODE cohort. After spatial preprocessing, regression of movement parameters, movement spikes, and scanner drift, low‐pass filtering and exclusion of subjects with high motion, CV and rCV maps were obtained and compared with respect to (A) clinical diagnosis (AD: n = 79; MCI: n = 113; SCD: n = 314; CON: n = 192) and cerebrospinal fluid Aβ42/40 (AD: n = 41; MCI: n = 64; SCD: n = 139; CON: n = 77); and (B) effects of vascular‐related lesions, here WMH.ResultThe CV and rCV of the precuneus and middle cingulum indicated increasingly reduced BOLD fluctuation across the clinical groups towards AD. Interestingly, we observed increases in rCV in the basal ganglia and frontal white matter in AD compared with CON. Of note, lower CSF Aβ42/40 (more pathological) was associated to reduced CV and rCV in the precuneus and with lower rCV in the right angular gyrus. Subjects with higher WMH volume showed widespread reductions of CV in white matter near the left angular gyrus and reduced rCV in large portions of white matter and subcortical gray matter.ConclusionThe AD spectrum exhibits altered BOLD fluctuations that are at least partially tied to actual amyloid differences. Larger WMH are associated with reduced BOLD signal fluctuations consistent with widespread white matter pathology ‐ beyond the effects of diagnosis. We argue that rCV is a useful complement to CV to detect these changes that might reflect cerebrovascular impairment.

Mapping of cerebrovascular reactivity using bold magnetic resonance imaging

Evidences suggested that both corpus callosum (CC) degeneration and alternations of homotopic inter-hemispheric functional connectivity (FC) are present in Alzheimer’s disease (AD). However, the associations between region-specific CC degeneration and homotopic inter-hemispheric FC and their relationships with memory deficits in AD remain uncharacterized. We hypothesized that selective CC degeneration is associated with memory impairment in AD and amnestic mild cognitive impairment (aMCI), which is mediated by homotopic inter-hemispheric functional dysconnectivity. Using structural magnetic resonance imaging (MRI) and task-free functional MRI, we assessed the CC volume and inter-hemispheric FC in 66 healthy controls, 41 aMCI and 41 AD. As expected, AD had CC degeneration and attenuated inter-hemispheric homotopic FC. Nevertheless, aMCI had relatively less severe CC degeneration (mainly in mid-anterior, central, and mid-posterior) and no reduction in inter-hemispheric homotopic FC. The degeneration of each CC sub-region was associated with specific inter-hemispheric homotopic functional disconnections in AD and aMCI. More importantly, impairment of inter-hemispheric homotopic FC partially mediated the association between CC (particularly the central and posterior parts) degeneration and memory deficit. Notably, these results remained after controlling for hippocampal volume. Our findings shed light on how CC degeneration and the related inter-hemispheric FC impact memory impairment in early stage of AD.

Perinatal stroke causes lifelong disability, particularly hemiparetic cerebral palsy. Arterial ischemic strokes (AIS) are large, cortical, and subcortical injuries acquired near birth due to acute occlusion of the middle cerebral artery. Periventricular venous infarctions (PVI) are smaller, subcortical strokes acquired prior to 34 weeks gestation involving injury to the periventricular white matter. Both stroke types can damage motor pathways, thus, we investigated resulting alterations in functional motor networks and probed function. We measured blood oxygen level dependent (BOLD) fluctuations at rest in 38 participants [10 arterial patients (age = 14.7 ± 4.1 years), 10 venous patients (age = 13.5 ± 3.7 years), and 18 typically developing controls (TDCs) (age = 15.3 ± 5.1 years)] and explored strength and laterality of functional connectivity in the motor network. Inclusion criteria included MRI-confirmed, unilateral perinatal stroke, symptomatic hemiparetic cerebral palsy, and 6-19 years old at time of imaging. Seed-based functional connectivity analyses measured temporal correlations in BOLD response over the whole brain using primary motor cortices as seeds. Laterality indices based on mean z-scores in lesioned and nonlesioned hemispheres explored laterality. In AIS patients, significant differences in both strength and laterality of motor network connections were observed compared with TDCs. In PVI patients, motor networks largely resembled those of healthy controls, albeit slightly weaker and asymmetric, despite subcortical damage and hemiparesis. Functional connectivity strengths were not related to motor outcome scores for either stroke group. This study serves as a foundation to better understand how resting-state fMRI can assess motor functional connectivity and potentially be applied to explore mechanisms of interventional therapies after perinatal stroke.

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.