BOLD Signal Research Articles

Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum

AbstractBackgroundInflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction.MethodLeveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aß42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory.ResultLower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers.ConclusionLower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.

Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum

AbstractBackgroundInflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction.MethodLeveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aβ42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory.ResultLower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers.ConclusionLower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.

The relationships between hippocampal cerebrovascular reactivity, hippocampal volume, and episodic memory in healthy ageing

AbstractBackgroundCerebrovascular biomarkers such as cerebrovascular reactivity (CVR) have previously been associated with episodic memory. However, the relationship between memory and regional CVR within the hippocampus is not well studied. Moreover, whether this association is affected by hippocampal volume remains to be investigated. This study investigated the associations between hippocampal physiology, structure, and memory in ageing.MethodData from 104 participants (Age: Mean = 77±4.9 years) of the ongoing Oxford Heart and Brain Study was analysed for this study. CVR was assessed by a compensatory change in the blood oxygenation level dependent magnetic resonance imaging (MRI) signal in response to a 5% CO2 challenge, hippocampus volume was measured by structural MRI, and episodic memory was assessed with the Hopkins Verbal Learning Test Revised (HVLT‐R).ResultMean hippocampal CVR decreased with age (β = ‐0.004, p = 0.006). Mean hippocampal CVR was positively associated with mean hippocampal volume (β = 0.11, p = 0.010), and this association was driven by the left hippocampus after correcting for age and sex. Higher hippocampal CVR was also associated with better performance on the HVLT (β = 13.8, p = 0.035). This association was fully mediated by hippocampal volume, suggesting a path from cerebrovascular reactivity to episodic memory (Sobel’s z = 2.16, p = 0.030, see Figure 1).ConclusionThis study presents novel findings showing that hippocampal CVR was associated with episodic memory, and this association was mediated by hippocampal volume. This suggests a pathway by which impairments in hippocampal CVR are associated with worse episodic memory via smaller hippocampal volumes.

Baseline cerebrovascular reactivity predicts longitudinal enlarged perivascular space burden in the basal ganglia among cognitively normal older adults

AbstractBackgroundIncreasing evidence suggests that enlarged perivascular spaces (ePVS) on magnetic resonance images (MRIs) are associated with cognitive dysfunction in aging. However, the etiology of ePVS remains unknown. Here we tested the possibility that cerebrovascular dysfunction, as assessed by an MRI measure of cerebrovascular reactivity (CVR), may contribute to ePVS development.Method79 cognitively normal, older adults (46 women, age range 60‐84) were recruited to undergo baseline MRI scanning and follow‐up scanning approximately 2.5 years later. Of the 79 participants scanned at baseline, 50 returned for follow‐up. Participants were scanned on a 3T Siemens Prisma scanner with a 64‐channel head coil. All scanning methods were identical across time points and included collection of T1‐weighted, T2‐weighted FLAIR, and quantitative susceptibility mapping (QSM) images. Cerebrovascular dysfunction was assessed using CVR, a measure of the ability of cerebrovasculature to dilate in response to vasoactive stimuli. Participants underwent blocked administration of breathing either room air or hypercapnic gas, while blood‐oxygen‐level‐dependent (BOLD) functional magnetic resonance imaging (fMRI) was performed. CVR values were computed for baseline scans in specific regions by dividing change in BOLD signal by change in end‐tidal CO2. Baseline and follow‐up ePVS counts were performed by a single rater who was blinded to participant demographics. ePVS were individually and manually counted using STRIVE criteria in a representative, axial slice of the basal ganglia (BGePVS) and centrum semiovale (CSePVS).ResultBGePVS and CSePVS significantly increased during the follow‐up period. Mixed effects models indicated that baseline basal ganglia CVR values significantly predicted increased BGePVS counts after controlling for age, sex, education, and time point (p = <0.001). Furthermore, this effect was present bilaterally: Baseline CVR in the left hemisphere predicted increased BGePVS in the left hemisphere (p = <0.001) and baseline CVR in the right hemisphere predicted increased BGePVS in the right hemisphere (p = <0.001). Conversely, there was no longitudinal relationship between baseline CVR and increased CSePVS (p = 0.449).ConclusionThese results demonstrate that low baseline CVR is a risk factor for later development of ePVS. Localization of these findings to the basal ganglia suggests that it is particularly vulnerable to cerebrovascular dysfunction.

Orientation representation in human visual cortices: contributions of non-visual information and action-related process.

Orientation processing in the human brain plays a crucial role in guiding grasping actions toward an object. Remarkably, despite the absence of visual input, the human visual cortex can still process orientation information. Instead of visual input, non-visual information, including tactile and proprioceptive sensory input from the hand and arm, as well as feedback from action-related processes, may contribute to orientation processing. However, the precise mechanisms by which the visual cortices process orientation information in the context of non-visual sensory input and action-related processes remain to be elucidated. Thus, our study examined the orientation representation within the visual cortices by analyzing the blood-oxygenation-level-dependent (BOLD) signals under four action conditions: direct grasp (DG), air grasp (AG), non-grasp (NG), and uninformed grasp (UG). The images of the cylindrical object were shown at +45° or - 45° orientations, corresponding to those of the real object to be grasped with the whole-hand gesture. Participants judged their orientation under all conditions. Grasping was performed without online visual feedback of the hand and object. The purpose of this design was to investigate the visual areas under conditions involving tactile feedback, proprioception, and action-related processes. To address this, a multivariate pattern analysis was used to examine the differences among the cortical patterns of the four action conditions in orientation representation by classification. Overall, significant decoding accuracy over chance level was discovered for the DG; however, during AG, only the early visual areas showed significant accuracy, suggesting that the object's tactile feedback influences the orientation process in higher visual areas. The NG showed no statistical significance in any area, indicating that without the grasping action, visual input does not contribute to cortical pattern representation. Interestingly, only the dorsal and ventral divisions of the third visual area (V3d and V3v) showed significant decoding accuracy during the UG despite the absence of visual instructions, suggesting that the orientation representation was derived from action-related processes in V3d and visual recognition of object visualization in V3v. The processing of orientation information during non-visually guided grasping of objects relies on other non-visual sources and is specifically divided by the purpose of action or recognition.

Abnormal functional activation during response inhibition in mild cognitive impairment: an fMRI study

AbstractBackgroundDeclines in response inhibition are observed both typical and atypical aging, i.e., mild cognitive impairment (MCI). Increased functional activation in frontoparietal regions during response inhibition has been interpreted to represent the emergence of a compensatory mechanism in older adulthood. While electrophysiology studies suggest the decline in response inhibition in MCI reflects a similar but amplified process as seen in normal aging this has not been examined thoroughly using functional MRI (fMRI).Method31 cognitively normal older adults (M age = 73.6, 9 male) and 22 adult patients with MCI (M age = 67.2, 14 male) performed a Go/NoGo task during an fMRI scan. Group differences in accuracy and reaction time were examined for Go and NoGo trials. Individual BOLD signal change during task fMRI was examined, then voxel‐wise group comparison was conducted for MCI vs. HC groups, using age, gender, education, and gray matter density as covariates. Permutation‐estimated cluster size at alpha <.05 was defined to correct for errors of multiple comparisons.ResultBehaviorally, the MCI group made significantly more errors during NoGo and Go trials (p<.001, p = .032, respectively), however, average reaction time did not differ significantly between groups. During NoGo trials, greater activation in the anterior default mode network (DMN), right dorsolateral prefrontal cortex (DLPFC), and motor areas was observed for MCI vs. HC, while during go trials, there was greater activation in DMN and right insula (corrected p<0.05). However, when Go vs. NoGo trials were examined, MCI showed more activation in right insula and DLPFC, but less activation in the motor area at trend level (p<0.05, uncorrected). While, there were no significant task performance differences between MCI subtypes (amnestic vs. non‐amnestic), amnestic MCI (aMCI) showed more activation in posterior DMN and dorsal attention area during NoGo trials (corrected p<0.05).ConclusionMCI demonstrated significantly greater activation during both Go and NoGo trials and made significantly more errors in performance during both trial types as well. While the MCI subtypes did not exhibit differences in performance on the task, the aMCI exhibited significantly greater activation in multiple regions. Our findings suggested inefficient DMN suppression during task performance in the MCI cohort, especially in the aMCI subgroup.

Abnormal functional activation during response inhibition in mild cognitive impairment: an fMRI study

AbstractBackgroundDeclines in response inhibition are observed both typical and atypical aging, i.e., mild cognitive impairment (MCI). Increased functional activation in frontoparietal regions during response inhibition has been interpreted to represent the emergence of a compensatory mechanism in older adulthood. While electrophysiology studies suggest the decline in response inhibition in MCI reflects a similar but amplified process as seen in normal aging this has not been examined thoroughly using functional MRI (fMRI).Methods31 cognitively normal older adults (M age = 73.6, 9 male) and 22 adult patients with MCI (M age = 67.2, 14 male) performed a Go/NoGo task during an fMRI scan. Group differences in accuracy and reaction time were examined for Go and NoGo trials. Individual BOLD signal change during task fMRI was examined, then voxel‐wise group comparison was conducted for MCI vs. HC groups, using age, gender, education, and gray matter density as covariates. Permutation‐estimated cluster size at alpha <.05 was defined to correct for errors of multiple comparisons.ResultsBehaviorally, the MCI group made significantly more errors during NoGo and Go trials (p<.001, p = .032, respectively), however, average reaction time did not differ significantly between groups. During NoGo trials, greater activation in the anterior default mode network (DMN), right dorsolateral prefrontal cortex (DLPFC), and motor areas was observed for MCI vs. HC, while during go trials, there was greater activation in DMN and right insula (corrected p<0.05). However, when Go vs. NoGo trials were examined, MCI showed more activation in right insula and DLPFC, but less activation in the motor area at trend level (p<0.05, uncorrected). While, there were no significant task performance differences between MCI subtypes (amnestic vs. non‐amnestic), amnestic MCI (aMCI) showed more activation in posterior DMN and dorsal attention area during NoGo trials (corrected p<0.05).ConclusionMCI demonstrated significantly greater activation during both Go and NoGo trials and made significantly more errors in performance during both trial types as well. While the MCI subtypes did not exhibit differences in performance on the task, the aMCI exhibited significantly greater activation in multiple regions. Our findings suggested inefficient DMN suppression during task performance in the MCI cohort, especially in the aMCI subgroup.

The impact of breathing patterns on CSF flow and global brain BOLD signal while awake: A study using real‐time phase‐contrast MRI and fast rsfMRI

AbstractBackgroundThe cardiac and respiratory cycles have been suggested as major drivers of cerebrospinal fluid(CSF) flow. The glymphatic system, one of the mechanisms for the clearance of amyloid‐beta and tau proteins, relies heavily on the movement(flow) of the CSF, and thus, investigating the forces that modulate the CSF flow is essential for understanding the glymphatic flux. Because breathing is trainable through exercise and self‐directed methods, various breathing methods may enhance the CSF flow.MethodReal‐time phase‐contrast MRI(pc‐MRI) was used to measure the CSF flow at the foramen magnum on a 3T. Fast resting‐state fMRI(rsfMRI;TR400ms) was conducted on a compact 3T. Under an IRB‐approved protocol, participants were instructed to breathe slowly and deeply, and subsequently switch to their spontaneous breathing. For rsfMRI data preprocessing, we performed motion correction, skull stripping, spatial smoothing(4mm), temporal filtering(0.01 to 0.1Hz), and linear and quadratic temporal trends removal. fMRI time courses were then normalized to Z‐score at each voxel before being averaged. On the pcMRI, the phase was summed in a CSF region‐of‐interest and plotted vs time. Additionally, we confirmed for possible confounding effects such as head motion or motion‐induced susceptibility changes.ResultrsfMRI findings showed that deep breathing promoted large oscillations in the CSF flow in the ventricles, while spontaneous breathing did not(Figure 1). Additionally, deep breathing resulted in large oscillations in lobar cortical regions. Similar results were observed in the pcMRI, with larger CSF velocity through the foramen magnum during the deep breathing compared to the spontaneous breathing(Figure 2A‐B). The cumulative summation result showed that the volume of CSF flow was increased during deep breathing(Figure 2C).ConclusionThis study provides new evidence that slow and deep breathing promotes CSF flow and global brain BOLD signal, which may be useful in promoting circulation in the brain. The study’s findings also open new avenues for research in the field of neurovascular coupling and mechanisms associated with glymphatic clearance. As hampered CSF flow and/or worsen glymphatic clearance have been shown to associate with pathological aging and dementia, including Alzheimer’s disease and Parkinson’s disease, future research is needed explore the potential of breathing training methods as a non‐pharmacological intervention to support brain health.

An easy-to-implement, non-invasive head restraint method for monkey fMRI

Functional magnetic resonance imaging (fMRI) in behaving monkeys has a strong potential to bridge the gap between human neuroimaging and primate neurophysiology. In monkey fMRI, to restrain head movements, researchers usually surgically implant a plastic head-post on the skull. Although time-proven to be effective, this technique could create burdens for animals, including a risk of infection and discomfort. Furthermore, the presence of extraneous objects on the skull, such as bone screws and dental cement, adversely affects signals near the cortical surface. These side effects are undesirable in terms of both the practical aspect of efficient data collection and the spirit of “refinement” from the 3R's. Here, we demonstrate that a completely non-invasive fMRI scan in awake monkeys is possible by using a plastic head mask made to fit the skull of individual animals. In all of the three monkeys tested, longitudinal, quantitative assessment of head movements showed that the plastic mask has effectively suppressed head movements, and we were able to obtain reliable retinotopic BOLD signals in a standard retinotopic mapping task. The present, easy-to-make plastic mask has a strong potential to simplify fMRI experiments in awake monkeys, while giving data that is as good as or even better quality than that obtained with the conventional head-post method.

A Preliminary Study of Brain Functional Magnetic Resonance Imaging in Text Reading and Comprehension.

Few studies have focused on the changes in human brain function activities caused by reading Chinese characters with different intelligibility and whether it can reflect the understanding and cognitive ability of the human brain. Task-fMRI based on Chinese character reading tasks with different intelligibility was used to explore activated brain regions and their cognitive changes. Volunteers were randomly recruited using advertisements. Forty volunteers were recruited based on strict inclusion and exclusion criteria, and 40 volunteers were recruited. Brain function data of 40 healthy right-handed volunteers in fuzzy/clear Chinese reading tasks were collected using a Siemens Skyra 3.0T magnetic resonance scanner. Data were preprocessed and statistically analyzed using the statistical software SPM12.0 to observe the activation of the cortex and analyze its characteristics and possible changes in cognitive function. Task-fMRI analysis: (1) The main brain regions activated in fuzzy/clear reading tasks were located in the occipital visual cortex (P < 0.001); (2) a paired sample t-test suggested that there was a significant difference in BOLD signals in the brain regions activated by fuzzy/clear reading tasks (P < 0.001, equiv Z = 4.25). Compared with the fuzzy reading task, the brain regions more strongly activated in the clear reading task were mainly located in the right superior frontal gyrus and the bilateral temporal lobe. Compared with the clear reading task, the brain region that was more strongly activated in the fuzzy reading task was mainly located in the right fusiform gyrus. Clear Chinese character information mainly activates the dorsal stream of the visual-spatial network. This reflects the information transmission of the brain after understanding the text content and is responsible for guiding and controlling attention. Fuzzy words that cannot provide clear text content activate the fusiform gyrus of the ventral stream of the visual-spatial network, strengthening the function of orthographic processing.

Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder — study protocol for a randomized clinical trial

BackgroundAnhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated.MethodsThis is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow.DiscussionThis study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options.Trial registrationClinicalTrials.gov NCT05347199. April 12, 2022.

Neural correlates of deceased-related attention during acute grief in suicide-related bereavement

BackgroundIndividuals who have lost a loved one to suicide demonstrate an attentional bias to deceased-related stimuli during early grief. Regulating attention toward reminders of the deceased during acute bereavement may be linked to grief trajectory and pathological grief development. Despite the potential prognostic importance, little is known about underlying neural circuitry correlates of deceased-related grief processing. The current study examines neural substrates of deceased-related attentional processing during acute grief in individuals bereaved by suicide. MethodsThirty-seven participants grieving the loss of a first-degree relative or partner to suicide in the prior six months, underwent functional magnetic resonance imaging (fMRI) while performing an emotional Stroop task using words related to the deceased and a living attachment figure, in order to examine neural correlates of deceased-specific attentional processing. Clinical interviews were conducted at baseline. ResultsDeceased-related attentional bias was associated with blood oxygen level-dependent (BOLD) activation in a brain network, including dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), orbitofrontal cortex (OFC), and insula. Greater activation of a bilateral prefrontal cluster during deceased-specific attention was negatively correlated with self-reported grief avoidance behaviors. LimitationsLack of non-suicide grief control and small sample size. ConclusionsThese data, if confirmed, indicate a neural network specific to deceased-related attention, and that cognitive control regions within this network appear to be related to grief avoidance behaviors during acute bereavement.

Neonatal neural responses to novelty related to behavioral inhibition at 1 year.

Behavioral inhibition (BI), an early-life temperament characterized by vigilant responses to novelty, is a risk factor for anxiety disorders. In this study, we investigated whether differences in neonatal brain responses to infrequent auditory stimuli relate to children's BI at 1 year of age. Using functional magnetic resonance imaging (fMRI), we collected blood-oxygen-level-dependent (BOLD) data from N = 45 full-term, sleeping neonates during an adapted auditory oddball paradigm and measured BI from n = 27 of these children 1 year later using an observational assessment. Whole-brain analyses corrected for multiple comparisons identified 46 neonatal brain regions producing novelty-evoked BOLD responses associated with children's BI scores at 1 year of age. More than half of these regions (n = 24, 52%) were in prefrontal cortex, falling primarily within regions of the default mode or frontoparietal networks or in ventromedial/orbitofrontal regions without network assignments. Hierarchical clustering of the regions based on their patterns of association with BI resulted in two groups with distinct anatomical, network, and response-timing profiles. The first group, located primarily in subcortical and temporal regions, tended to produce larger early oddball responses among infants with lower subsequent BI. The second group, located primarily in prefrontal cortex, produced larger early oddball responses among infants with higher subsequent BI. These results provide preliminary insights into brain regions engaged by novelty in infants that may relate to later BI. The findings may inform understanding of anxiety disorders and guide future research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Characterizing systemic physiological effects on the blood oxygen level dependent signal of resting-state fMRI in time-frequency space using wavelets.

Systemic physiological dynamics, such as heart rate variability (HRV) and respiration volume per time (RVT), are known to account for significant variance in the blood oxygen level dependent (BOLD) signal of resting-state functional magnetic resonance imaging (rsfMRI). However, synchrony between these cardiorespiratory changes and the BOLD signal could be due to neuronal (i.e., autonomic activity inducing changes in heart rate and respiration) or vascular (i.e., cardiorespiratory activity facilitating hemodynamic changes and thus the BOLD signal) effects and the contributions of these effects may differ spatially, temporally, and spectrally. In this study, we characterize these brain-body dynamics using a wavelet analysis in rapidly sampled rsfMRI data with simultaneous pulse oximetry and respiratory monitoring of the Human Connectome Project. Our time-frequency analysis across resting-state networks (RSNs) revealed differences in the coherence of the BOLD signal and heartbeat interval (HBI)/RVT dynamics across frequencies, with unique profiles per network. Somatomotor (SMN), visual (VN), and salience (VAN) networks demonstrated the greatest synchrony with both systemic physiological signals when compared to other networks; however, significant coherence was observed in all RSNs regardless of direct autonomic involvement. Our phase analysis revealed distinct frequency profiles of percentage of time with significant coherence between BOLD and systemic physiological signals for different phase offsets across RSNs, suggesting that the phase offset and temporal order of signals varies by frequency. Lastly, our analysis of temporal variability of coherence provides insight on potential influence of autonomic state on brain-body communication. Overall, the novel wavelet analysis enables an efficient characterization of the dynamic relationship between cardiorespiratory activity and the BOLD signal in spatial, temporal, and spectral dimensions to inform our understanding of autonomic states and improve our interpretation of the BOLD signal.

On a framework of data assimilation for hyperparameter estimation of spiking neuronal networks

When handling real-world data modeled by a complex network dynamical system, the number of the parameters is often much more than the size of the data. Therefore, in many cases, it is impossible to estimate these parameters and the exact value of each parameter is frequently less interesting than the distribution of the parameters. In this paper, we aim to estimate the distribution of the parameters in the mesoscopic neuronal network model from the macroscopic experimental data, for example, the BOLD (blood oxygen level dependent) signal. Herein, we assume that the parameters of the neurons and synapses are inhomogeneous but independently and identically distributed from certain distributions with unknown hyperparameters. Thus, we estimate these hyperparameters of the distributions of the parameters, instead of estimating the parameters themselves. We formulate this problem under the framework of data assimilation and hierarchical Bayesian method and present an efficient method named Hierarchical Data Assimilation (HDA) to conduct the statistical inference on the neuronal network model with the BOLD signal data simulated by the hemodynamic model. We consider the Leaky Integral-Fire (LIF) neuronal networks with four synapses and show that the proposed algorithm can estimate the BOLD signals and the hyperparameters with high preciseness. In addition, we discuss the influence on the performance of the algorithm configuration and the LIF network model setup.

Levodopa may modulate specific speech impairment in Parkinson's disease: an fMRI study.

Hypokinetic dysarthria (HD) is a difficult-to-treat symptom affecting quality of life in patients with Parkinson's disease (PD). Levodopa may partially alleviate some symptoms of HD in PD, but the neural correlates of these effects are not fully understood. The aim of our study was to identify neural mechanisms by which levodopa affects articulation and prosody in patients with PD. Altogether 20 PD patients participated in a task fMRI study (overt sentence reading). Using a single dose of levodopa after an overnight withdrawal of dopaminergic medication, levodopa-induced BOLD signal changes within the articulatory pathway (in regions of interest; ROIs) were studied. We also correlated levodopa-induced BOLD signal changes with the changes in acoustic parameters of speech. We observed no significant changes in acoustic parameters due to acute levodopa administration. After levodopa administration as compared to the OFF dopaminergic condition, patients showed task-induced BOLD signal decreases in the left ventral thalamus (p = 0.0033). The changes in thalamic activation were associated with changes in pitch variation (R = 0.67, p = 0.006), while the changes in caudate nucleus activation were related to changes in the second formant variability which evaluates precise articulation (R = 0.70, p = 0.003). The results are in line with the notion that levodopa does not have a major impact on HD in PD, but it may induce neural changes within the basal ganglia circuitries that are related to changes in speech prosody and articulation.

Structural and Physiological Modeling (SAPM) for the Analysis of Functional MRI Data Applied to a Study of Human Nociceptive Processing.

A novel method has been developed for analyzing connectivity between regions based on functional magnetic resonance imaging (fMRI) data. This method, termed structural and physiological modeling (SAPM), combines information about blood oxygenation-level dependent (BOLD) responses, anatomy, and physiology to model coordinated signaling across networks of regions, including input and output signaling from each region and whether signaling is predominantly inhibitory or excitatory. The present study builds on a prior proof-of-concept demonstration of the SAPM method by providing evidence for the choice of network model and anatomical sub-regions, demonstrating the reproducibility of the results and identifying statistical thresholds needed to infer significance. The method is further validated by applying it to investigate human nociceptive processing in the brainstem and spinal cord and comparing the results to the known neuroanatomy, including anatomical regions and inhibitory and excitatory signaling. The results of this analysis demonstrate that it is possible to obtain reliable information about input and output signaling from anatomical regions and to identify whether this signaling has predominantly inhibitory or excitatory effects. SAPM provides much more detailed information about neuroanatomy than was previously possible based on fMRI data.

Abstract 15900: Probing Mitochondrial Dysfunction in Mouse Hearts With Doxorubicin-Induced Cardiotoxicity Using Ungated 4D Oxy-Wavelet MRI

Introduction: Despite advances in cancer therapy greatly improving patient survival, more than two-thirds of cancer survivors will still face serious life-threatening cardiomyopathy caused by anti-cancer anthracyclines. Doxorubicin (Dox), a well-known, well studied anthracycline, is a major cause for long-term morbidity and mortality among cancer survivors. Pertinent to this issue is the lack of non-invasive imaging tools that can detect DOX induced cardiomyopathy before irreversible tissue damage is done. Current research of cellular mechanisms underlying DOX-induced cardiotoxicity has shown that mitochondrial dysfunction are central to this cardiomyopathy. Hypothesis: We hypothesize that this mitochondrial dysfunction precedes clinical changes in cardiac strain and left-ventricle ejection fraction. Methods: To probe mitochondrial function non-invasively, we use motion-and-time resolved 4D functional MRI, coined 4D Oxy-Wavelet. Our methodology can capture dynamic changes in the blood oxygenation level dependent (BOLD) signal with high spatiotemporal resolution. Our cyclic hypoxia challenge leverages the need for in-tact mitochondrial function to maintain homeostatic oxygenation during hypoxia. We combine our 4D-fMRI methodology with a cyclic hypoxia challenge to stress-test the mitochondria in a mouse model of DOX-induced cardiotoxicity. We use a novel time-frequency analysis of the event-driven BOLD response to automate the detection of mitochondrial dysfunction in-vivo. Results: C57BL6/J were given Dox over the course of one week. 4D oxy-wavelet MRI was performed at baseline, day 1, 3, 4, and 7 to evaluate the ability to rapidly detect acute DOX induced cardiotoxicity. We found that as early as day one post exposure, mice exhibited a passive response to the hypoxia challenge, representing an inability to maintain homeostatic oxygen and underlying mitochondria dysfunction, that was maintained through this acute period.

Abstract 11433: Elevated Vascular Endothelial Growth Factor A is Associated With Disruption of Default Network Connectivity

Introduction: Vascular Endothelial Growth Factor A (VEGF-A) is an angiogenic signaling protein involved in the maintenance of the cerebral vasculature. VEGF-A may play a role in the pathogenesis of Alzheimer’s disease and vascular dementia; however, whether elevated VEGF-A levels indicate a pathophysiolocal response or protective mechanism remains unclear. No prior study has explored whether VEGF-A levels may be associated with changes in functional connectivity among brain regions prior to the development of cognitive decline. Hypothesis: Disruption of the default network often precedes the development of cognitive changes. In a sample of older adults, we hypothesized that VEGF-A levels may be associated with default network connectivity, indicating early involvement of VEGF-A in disease processes. Methods: Forty-six independently living older adults (mean age = 72.0 years; SD = 6.4; 34.8% male) free of dementia or clinical stroke underwent venipuncture and brain MRI. Plasma was assayed for VEGF-A. Using resting state functional MRI, blood-oxygen level dependent (BOLD) time series from all voxels in each region of interest (ROI) was averaged to determine mean ROI activity. Medial prefrontal cortex, lateral parietal cortex and precuneus cortex ROIs comprised the default network. Results: Accounting for age and sex, multiple linear regression analysis revealed a significant negative association between VEGF-A levels and default mode network connectivity (B =-.0007, 95% CI (-.0012, -.0002), p = .0096). This association persisted after adjusting for APOE4 carrier status and Framingham score. A significant association was present in both APOE4 carriers (p = .019) and non-carriers (p = .029). Conclusions: Prior studies evaluating the association between VEGF-A levels and cognition have been conflicted. This study is the first to examine whether VEGF-A may be linked to early changes in brain network connectivity which precede cognitive decline. These findings suggest that VEGF-A may be elevated early in the progression of neurocognitive disorders. Whether higher levels of VEGF-A contribute to the pathogenesis of neurocognitive disorders or play a protective role in persevering cognitive function warrants further investigation.

Whole-brain multivariate hemodynamic deconvolution for functional MRI with stability selection

Conventionally, analysis of functional MRI (fMRI) data relies on available information about the experimental paradigm to establish hypothesized models of brain activity. However, this information can be inaccurate, incomplete or unavailable in multiple scenarios such as resting-state, naturalistic paradigms or clinical conditions. In these cases, blind estimates of neuronal-related activity can be obtained with paradigm-free analysis methods such as hemodynamic deconvolution. Yet, current formulations of the hemodynamic deconvolution problem have three important limitations: (1) their efficacy strongly depends on the appropriate selection of regularization parameters, (2) being univariate, they do not take advantage of the information present across the brain, and (3) they do not provide any measure of statistical certainty associated with each detected event. Here we propose a novel approach that addresses all these limitations. Specifically, we introduce multivariate sparse paradigm free mapping (Mv-SPFM), a novel hemodynamic deconvolution algorithm that operates at the whole brain level and adds spatial information via a mixed-norm regularization term over all voxels. Additionally, Mv-SPFM employs a stability selection procedure that removes the need to select regularization parameters and also lets us obtain an estimate of the true probability of having a neuronal-related BOLD event at each voxel and time-point based on the area under the curve (AUC) of the stability paths. Besides, we present a formulation tailored for multi-echo fMRI acquisitions (MvME-SPFM), which allows us to better isolate fluctuations of BOLD origin on the basis of their linear dependence with the echo time (TE) and to assign physiologically interpretable units (i.e., changes in the apparent transverse relaxation ΔR2∗) to the resulting deconvolved events. Remarkably, we demonstrate that Mv-SPFM achieves comparable performance even when using a single-echo formulation. We demonstrate that this algorithm outperforms existing state-of-the-art deconvolution approaches, and shows higher spatial and temporal agreement with the activation maps and BOLD signals obtained with a standard model-based linear regression approach, even at the level of individual neuronal events. Furthermore, we show that by employing stability selection, the performance of the algorithm depends less on the selection of temporal and spatial regularization parameters λ and ρ. Consequently, the proposed algorithm provides more reliable estimates of neuronal-related activity, here in terms of ΔR2∗, for the study of the dynamics of brain activity when no information about the timings of the BOLD events is available. This algorithm will be made publicly available as part of the splora Python package.