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INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Prior studies suggest that obsessive–compulsive disorder (OCD) can cause both anatomical and functional variations in the brain, but to date, altered functional synchronization between two functional hemispheres remains unclear in OCD patients. Voxel‐mirrored homotopic connectivity (VMHC) is defined as the temporal correlation of spontaneous low‐frequency blood oxygenation level‐dependent signal fluctuations across mirror regions of hemisphere revealing the homotopic connectivity between each voxel in one hemisphere and its mirrored counterpart in the contralateral hemisphere. To investigate the alterations of brain regional function and VMHC in patients with OCD, the current study enrolled 103 OCD patients and 118 healthy controls, undergoing resting‐state functional magnetic resonance imaging. Compared to healthy controls (HCs), patients had decreased VMHC in bilateral cerebellum, lingual and fusiform gyrus; bilateral paracentral lobule, pre and postcentral gyrus; and bilateral superior and middle temporal gyrus, putamen and bilateral precuneus without global signal regression. And we found mostly similar results after regressing global signals; apart from the regions mentioned above, decreased in bilateral cuneus and calcarine was also showed. Furthermore, the mean VMHC values of the left cerebellum were negatively correlated with the obsession scores (ρ = −.204, π =.039). The decreased values in right fusiform and putamen were negatively correlated with duration of disease (ρ = −.205, π =.038; ρ = −.196, π =.047). We confirmed a significant VMHC reduction in OCD patients in broad areas. Our findings suggest that the patients tend to disconnect information exchange across hemispheres. [ABSTRACT FROM AUTHOR]

Cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) signal measurements make it possible to estimate steady-state changes in the cerebral metabolic rate of oxygen (CMRO2) with a calibrated BOLD method. However, extending this approach to measure the dynamics of CMRO2 requires an additional assumption: that deoxygenated cerebral blood volume (CBVdHb) follows CBF in a predictable way. A test-case for this assumption is the BOLD post-stimulus undershoot, for which one proposed explanation is a strong uncoupling of flow and blood volume with an elevated level of CBVdHb during the post-stimulus period compared to baseline due to slow blood volume recovery (Balloon Model). A challenge in testing this model is that CBVdHb differs from total blood volume, which can be measured with other techniques. In this study, the basic hypothesis of elevated CBVdHb during the undershoot was tested, based on the idea that the BOLD signal change when a subject switches from breathing a normoxic gas to breathing a hyperoxic gas is proportional to the absolute CBVdHb. In 19 subjects (8F), dual-echo BOLD responses were measured in primary visual cortex during a flickering radial checkerboard stimulus in normoxia, and the identical experiment was repeated in hyperoxia (50% O2/balance N2). The BOLD signal differences between normoxia and hyperoxia for the pre-stimulus baseline, stimulus, and post-stimulus periods were compared using an equivalent BOLD signal calculated from measured R2* changes to eliminate signal drifts. Relative to the pre-stimulus baseline, the average BOLD signal change from normoxia to hyperoxia was negative during the undershoot period (p = 0.0251), consistent with a reduction of CBVdHb and contrary to the prediction of the Balloon Model. Based on these results, the BOLD post-stimulus undershoot does not represent a case of strong uncoupling of CBVdHb and CBF, supporting the extension of current calibrated BOLD methods to estimate the dynamics of CMRO2.

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis., Methods: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes., Results: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function., Discussion: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID., Highlights: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Arterial Spin Labeling (ASL) perfusion image series have recently been utilized for functional connectivity (FC) analysis in healthy volunteers and children with autism spectrum disorders (ASD). Noise reduction by using nuisance variables has been shown to be necessary to minimize potential confounding effects of head motion and physiological signals on BOLD based FC analysis. The purpose of the present study is to systematically evaluate the effectiveness of different noise reduction strategies (NRS) using nuisance variables to improve perfusion based FC analysis in two cohorts of healthy adults using state of the art 3D background-suppressed (BS) GRASE pseudo-continuous ASL (pCASL) and dual-echo 2D-EPI pCASL sequences. Five different NRS were performed in healthy volunteers to compare their performance. We then compared seed-based FC analysis using 3D BS GRASE pCASL in a cohort of 12 children with ASD (3f/9m, age 12.8 ± 1.3 years) and 13 typically developing (TD) children (1f/12m; age 13.9 ± 3 years) in conjunction with NRS. Regression of different combinations of nuisance variables affected FC analysis from a seed in the posterior cingulate cortex (PCC) to other areas of the default mode network (DMN) in both BOLD and pCASL data sets. Consistent with existing literature on BOLD-FC, we observed improved spatial specificity after physiological noise reduction and improved long-range connectivity using head movement related regressors. Furthermore, 3D BS GRASE pCASL shows much higher temporal SNR compared to dual-echo 2D-EPI pCASL and similar effects of noise reduction as those observed for BOLD. Seed-based FC analysis using 3D BS GRASE pCASL in children with ASD and TD children showed that noise reduction including physiological and motion related signals as nuisance variables is crucial for identifying altered long-range connectivity from PCC to frontal brain areas associated with ASD. This is the first study that systematically evaluated the effects of different NRS on ASL based FC analysis. 3D BS GRASE pCASL is the preferred ASL sequence for FC analysis due to its superior temporal SNR. Removing physiological noise and motion parameters is critical for detecting altered FC in neurodevelopmental disorders such as ASD.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertional malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction. Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA. Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS. Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases. [ABSTRACT FROM AUTHOR]

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertional malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.

Duchenne muscular dystrophy (DMD) is characterized by a progressive replacement of muscle by fat and fibrous tissue, muscle weakness, and loss of functional abilities. Impaired vasodilatory and blood flow responses to muscle activation have also been observed in DMD and associated with mislocalization of neuronal nitric oxide synthase mu (nNOSμ) from the sarcolemma. The objective of this study was to determine whether the postcontractile blood oxygen level-dependent (BOLD) MRI response is impaired in DMD and correlated with established markers of disease severity in DMD, including MRI muscle fat fraction (FF) and clinical functional measures. Young boys with DMD (n = 16, 5-14 yr) and unaffected controls (n = 16, 5-14 yr) were evaluated using postcontractile BOLD, FF, and functional assessments. The BOLD response was measured following five brief (2 s) maximal voluntary dorsiflexion contractions, each separated by 1 min of rest. FFs from the anterior compartment lower leg muscles were quantified via chemical shift-encoded imaging. Functional abilities were assessed using the 10 m walk/run and the 6-min walk distance (6MWD). The peak BOLD responses in the tibialis anterior and extensor digitorum longus were reduced (P < 0.001) in DMD compared with controls. Furthermore, the anterior compartment peak BOLD response correlated with function (6MWD ρ = 0.87, P < 0.0001; 10 m walk/run time ρ = -0.78, P < 0.001) and FF (ρ = -0.52, P = 0.05). The reduced postcontractile BOLD response in DMD may reflect impaired microvascular function. The relationship observed between the postcontractile peak BOLD response and functional measures and FF suggests that the BOLD response is altered with disease severity in DMD. NEW & NOTEWORTHY This study examined the postcontractile blood oxygen level-dependent (BOLD) response in boys with Duchenne muscular dystrophy (DMD) and unaffected controls, and correlated this measure to markers of disease severity. Our findings indicate that the postcontractile BOLD response is impaired in DMD after brief muscle contractions, is correlated to disease severity, and may be valuable to implement in future studies to evaluate treatments targeting microvascular function in DMD. [ABSTRACT FROM AUTHOR]

Recent studies from our group and others using quantitative fMRI methods have found that variations of the coupling ratio of blood flow (CBF) and oxygen metabolism (CMRO2) responses to a stimulus have a strong effect on the BOLD response. Across a number of studies an empirical pattern is emerging in the way CBF and CMRO2 changes are coupled to neural activation: if the stimulus is modulated to create a stronger response (e.g., increasing stimulus contrast), CBF is modulated more than CMRO2; on the other hand, if the brain state is altered such that the response to the same stimulus is increased (e.g., modulating attention, adaptation, or excitability), CMRO2 is modulated more than CBF. Because CBF and CMRO2 changes conflict in producing BOLD signal changes, this finding has an important implication for conventional BOLD-fMRI studies: the BOLD response exaggerates the effects of stimulus variation but is only weakly sensitive to modulations of the brain state that alter the response to a standard stimulus. A speculative hypothesis is that variability of the coupling ratio of the CBF and CMRO2 responses reflects different proportions of inhibitory and excitatory evoked activity, potentially providing a new window on neural activity in the human brain.

Functional connectivity MRI (fcMRI) is an fMRI method that examines the connectivity of different brain areas based on the correlation of BOLD signal fluctuations over time. Temporal Lobe Epilepsy (TLE) is the most common type of adult epilepsy and involves multiple brain networks. The default mode network (DMN) is involved in conscious, resting state cognition and is thought to be affected in TLE where seizures cause impairment of consciousness. The DMN in epilepsy was examined using seed based fcMRI. The anterior and posterior hubs of the DMN were used as seeds in this analysis. The results show a disconnection between the anterior and posterior hubs of the DMN in TLE during the basal state. In addition, increased DMN connectivity to other brain regions in left TLE along with decreased connectivity in right TLE is revealed. The analysis demonstrates how seed-based fcMRI can be used to probe cerebral networks in brain disorders such as TLE.

Functional MRI is increasingly being used in the assessment of brain activation and connectivity following stroke. Many of these studies rely on the Blood Oxygenation Level Dependent (BOLD) contrast. However, the stability, as well as the accuracy of the BOLD response to motor task in the ipsilesional hemisphere, remains ambiguous. In this work, the BOLD signal acquired from both healthy and affected hemispheres was analyzed in 7-year-old children who sustained a Neonatal Arterial Ischemic Stroke (NAIS). Accordingly, a repetitive motor task of the contralesional and the ipsilesional hands was performed by 33 patients with unilateral lesions. These patients were divided into two groups: those without cerebral palsy (NAIS), and those with cerebral palsy (CP). The BOLD signal time course was obtained from distinctly defined regions of interest (ROIs) extracted from the functional activation maps of 30 healthy controls with similar age and demographic characteristics as the patients. An ROI covering both the primary motor cortex (M1) and the primary somatosensory cortex (S1) was also tested. Compared with controls, NAIS patients without CP had similar BOLD amplitude variation for both the contralesional and the ipsilesional hand movements. However, in the case of NAIS patients with CP, a significant difference in the averaged BOLD amplitude was found between the healthy and affected hemisphere. In both cases, no progressive attenuation of the BOLD signal amplitude was observed throughout the task epochs. Besides, results also showed a correlation between the BOLD signal percentage variation of the lesioned hemisphere and the dexterity level. These findings suggest that for patients who sustained a NAIS with no extensive permanent motor impairment, BOLD signal-based data analysis can be a valuable tool for the evaluation of functional brain networks.

Quantitative functional magnetic resonance imaging methods make it possible to measure cerebral oxygen metabolism (CMRO2) in the human brain. Current methods require the subject to breathe special gas mixtures (hypercapnia and hyperoxia). We tested a noninvasive suite of methods to measure absolute CMRO2 in both baseline and dynamic activation states without the use of special gases: arterial spin labeling (ASL) to measure baseline and activation cerebral blood flow (CBF), with concurrent measurement of the blood oxygenation level dependent (BOLD) signal as a dynamic change in tissue R2*; VSEAN to estimate baseline O2 extraction fraction (OEF) from a measurement of venous blood R2, which in combination with the baseline CBF measurement yields an estimate of baseline CMRO2; and FLAIR-GESSE to measure tissue R2′ to estimate the scaling parameter needed for calculating the change in CMRO2 in response to a stimulus with the calibrated BOLD method. Here we describe results for a study sample of 17 subjects (8 female, mean age = 25.3 years, range 21–31 years). The primary findings were that OEF values measured with the VSEAN method were in good agreement with previous PET findings, while estimates of the dynamic change in CMRO2 in response to a visual stimulus were in good agreement between the traditional hypercapnia calibration and calibration based on R2′. These results support the potential of gas-free methods for quantitative physiological measurements.

Background: The estimated glomerular filtration rate (eGFR) is frequently used to monitor progression of kidney disease. Multiple values have to be obtained, sometimes over years to determine the rate of decline in kidney function. Recent data suggest that functional MRI (fMRI) methods may be able to predict loss of eGFR. In a prior study, baseline data with multi-parametric MRI in individuals with diabetes and moderate CKD was reported. This report extends our prior observations in order to evaluate the temporal variability of the fMRI measurements over 36 months and their association with annual change in eGFR. Methods: Twenty-four subjects with moderate CKD completed 3 sets of MRI scans over a 36-month period. Blood oxygenation level-dependent (BOLD), arterial spin labeling perfusion, and diffusion MRI images were acquired using a 3 T scanner. Coefficients of variation was used to evaluate variability between subjects at each time point and temporal variability within each subject. We have conducted mixed effects models to examine the trajectory change in GFR over time using time and MRI variables as fixed effects and baseline intercept as random effect. Associations of MRI image markers with annual change in eGFR were evaluated. Results: Multi-parametric functional renal MRI techniques in individuals with moderate CKD showed higher temporal variability in R2* of medulla compared to healthy individuals. This was consistent with the significant lower R2* in medulla observed at 36 months compared to baseline values. The results of linear mixed model showing that R2*_Medulla was the only predictor associated with change in eGFR over time. Furthermore, a significant association of medullary R2* with annual loss of eGFR was observed at all the 3 time points. Conclusions: The lower R2* values and the higher temporal variability in the renal medulla over time suggest the ability to monitor progressive CKD. These were confirmed by the fact that reduced medullary R2* was associated with higher annual loss in eGFR. These data collectively emphasize the need for inclusion of medulla in the analysis of renal BOLD MRI studies. [ABSTRACT FROM AUTHOR]

Functional MRI is increasingly being used in the assessment of brain activation and connectivity following stroke. Many of these studies rely on the Blood Oxygenation Level Dependent (BOLD) contrast. However, the stability, as well as the accuracy of the BOLD response to motor task in the ipsilesional hemisphere, remains ambiguous. In this work, the BOLD signal acquired from both healthy and affected hemispheres was analyzed in 7-year-old children who sustained a Neonatal Arterial Ischemic Stroke (NAIS). Accordingly, a repetitive motor task of the contralesional and the ipsilesional hands was performed by 33 patients with unilateral lesions. These patients were divided into two groups: those without cerebral palsy (NAIS), and those with cerebral palsy (CP). The BOLD signal time course was obtained from distinctly defined regions of interest (ROIs) extracted from the functional activation maps of 30 healthy controls with similar age and demographic characteristics as the patients. An ROI covering both the primary motor cortex (M1) and the primary somatosensory cortex (S1) was also tested. Compared with controls, NAIS patients without CP had similar BOLD amplitude variation for both the contralesional and the ipsilesional hand movements. However, in the case of NAIS patients with CP, a significant difference in the averaged BOLD amplitude was found between the healthy and affected hemisphere. In both cases, no progressive attenuation of the BOLD signal amplitude was observed throughout the task epochs. Besides, results also showed a correlation between the BOLD signal percentage variation of the lesioned hemisphere and the dexterity level. These findings suggest that for patients who sustained a NAIS with no extensive permanent motor impairment, BOLD signal-based data analysis can be a valuable tool for the evaluation of functional brain networks. [ABSTRACT FROM AUTHOR]

Zhi-Ming Pan,1 Hai-Jun Li,1 Jing Bao,1 Nan Jiang,1 Qing Yuan,1 Shelby Freeberg,2 Pei-Wen Zhu,1 Lei Ye,1 Ming-Yang Ma,1 Xin Huang,1 Yi Shao1 1Department of Ophthalmology and Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Ophthalmology, University of Florida, Gainesville, FL, USA Objective: Many previous studies have reported that pain symptoms can lead to significant brain function and anatomical changes, whereas the intrinsic brain activity changes in acute eye pain (EP) patients remain unknown. Using the amplitude of low-frequency fluctuation (ALFF) method, this study aimed to evaluate the spontaneous brain activity alterations and their relationships with clinical features in acute EP patients.Participants and methods: A total of 20 patients with EP (15 males and 5 females) and 20 healthy controls (HCs; 15 males and 5 females) closely matched in age, sex, and education underwent resting-state functional magnetic resonance imaging scans. The ALFF method was applied to assess spontaneous brain activity changes. The ALFF values of the EP patients were distinguished from those of the HCs using a receiver operating characteristic curve. Pearson’s correlation analysis was used to investigate the relationships between the mean ALFF signal values from many brain regions and the clinical features in EP patients.Results: Compared with the HCs, acute EP patients had significantly lower ALFF in the left and right precentral/postcentral gyrus and left precuneus. In contrast, acute EP patients showed higher ALFF values in the right and left parahippocampal gyri and left caudate. However, no relationship was observed between the mean ALFF signal values from the different areas and clinical manifestations in the acute EP patients.Conclusion: We demonstrated that acute EP patients showed abnormal intrinsic brain activities in the precentral/postcentral gyrus and limbic system, which might provide useful information for explaining neural mechanisms in EP patients. Keywords: eye pain, ALFF, blood oxygenation level dependent, resting state, functional magnetic resonance imaging

Abstract Background Cognitive decline poses a great concern to elderly people and their families. In addition to pharmacological therapies, several varieties of nonpharmacological intervention have been developed. Most training trials proved that a well-organized task is clinically effective in cognition improvement. Main body We will first review clinical trials of cognitive training for healthy elders, MCI and AD patients, respectively. Besides, potential neuroprotective and compensatory mechanisms in animal models of AD are discussed. Despite controversy, cognitive training has promising effect on cognitive ability. In animal model of AD, environmental enrichment showed beneficial effect for cognitive ability, as well as neuronal plasticity. Neurotrophin, neurotransmitter and neuromodulator signaling pathway were also involved in the process. Well-designed cognitive activity could benefit cognitive function, and thus life quality of patients and their families. Conclusion The positive effects of cognitive activity is closely related with neural plasticity, neurotrophin, neurotransmitter and neuromodulator signaling pathway changes.

Functional magnetic resonance imaging (fMRI) is commonly thought to be too slow to capture any neural dynamics faster than 0.1 Hz. However, recent findings demonstrate the feasibility of detecting fMRI activity at higher frequencies beyond 0.2 Hz. The origin, reliability, and generalizability of fast fMRI responses are still under debate and await confirmation through animal experiments with fMRI and invasive electrophysiology. Here, we acquired single-echo and multi-echo fMRI, as well as local field potentials, from anesthetized rat brains given gastric electrical stimulation modulated at 0.2, 0.4 and 0.8 Hz. Such gastric stimuli could drive widespread fMRI responses at corresponding frequencies from the somatosensory and cingulate cortices. Such fast fMRI responses were linearly dependent on echo times and thus indicative of blood oxygenation level dependent nature (BOLD). Local field potentials recorded during the same gastric stimuli revealed transient and phase-locked broadband neural responses, preceding the fMRI responses by as short as 0.5 s. Taken together, these results suggest that gastric stimulation can drive widespread and rapid fMRI responses of BOLD and neural origin, lending support to the feasibility of using fMRI to detect rapid changes in neural activity up to 0.8 Hz under visceral stimulation. • Gastric electrical stimuli could drive fast-fMRI responses up to 0.8 Hz. • The fast fMRI responses are linearly dependent on echo time, and thus blood oxygenation level dependent. • The fast fMRI responses follow transient and broadband neural responses in the somatosensory cortex. [ABSTRACT FROM AUTHOR]